tbuckley/cabot-search huggingface dataset:
EAPH-14. MOLECULAR BIOLOGY AND PHASE I STUDY OF GM-CSF AND INTRATHECAL TRASTUZUMAB IN CHILDREN WITH RECURRENT POSTERIOR FOSSA EPENDYMOMA
Authors: Kathleen Dorris, Melissa Widener, Vladimir Amani, Andrew Donson, Debra Schissel, Brent O’Neill, Todd Hankinson, Michael Handler, Margaret Macy, Nicholas Foreman
Journal: Neuro-Oncology (2018)

Posterior fossa ependymoma (PF EPN) is a pediatric central nervous system malignancy that has poor outcome to standard therapeutic approaches. The majority of PF EPN tumors have increased HER2 expression. Trastuzumab is a monoclonal antibody that targets HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor cell proliferation. The combination of trastuzumab and GM-CSF has been shown to trigger antibody-dependent cell cytotoxicity in vitro in PF EPN cell lines. Due to reduced blood-brain barrier penetration of trastuzumab, intrathecal (IT) administration is an attractive method for delivery for treatment of recurrent PF-EPN. Children aged 1–21 years with relapsed PF EPN and no CSF obstruction on imaging are eligible for the Phase I institutional trial at Children’s Hospital Colorado. Stratum A involves IT trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-care surgical resection. Stratum B involves a 3 + 3 phase I design with serial IT trastuzumab doses, each preceded by 3 days of GM-CSF, to establish the MTD for IT trastuzumab. Three patients (1:2; male:female) have been enrolled in Stratum A at trastuzumab Dose Level 1 (40 mg). Median age at enrollment is 8.8 years (range, 4.2–20.0 years). 2/3 tumors tested after pre-surgical trastuzumab and GM-CSF had detectable trastuzumab by mass spectroscopy. No adverse events at least possibly related to study therapy have occurred. IT trastuzumab penetrates PF EPN tumor tissue. Stratum A remains open to enrollment for eligible patients who have clinical indication for surgical resection. Based on Stratum A results, Stratum B is now also open to accrual.
QOL-09. EMOTION RECOGNITION IN PEDIATRIC BRAIN TUMOR PATIENTS: VIEWING PATTERNS AND WHITE MATTER STRUCTURE
Authors: Iska Moxon-Emre, Eric Bouffet, Suzanne Laughlin, Jovanka Skocic, Cynthia de Medeiros, Donald J Mabbott
Journal: Neuro-Oncology (2018)

Pediatric brain tumor patients display emotion recognition deficits, and eye-movement monitoring might help explain why. Identifying facial emotions is thought to rely on white matter (WM) that connects posterior, limbic and frontal brain regions. Thus, we examined if emotion recognition deficits are related to viewing patterns and to WM. 22 patients treated for posterior fossa (PF) brain tumors and 12 healthy children participated in this study at SickKids (Toronto, Ontario). Participants completed the Diagnostic Analysis of Nonverbal Accuracy (DANVA-2), a computerized task that measures facial emotion recognition using photographs, while their eye-movements were recorded. Diffusion tensor imaging (DTI) was used to assess fractional anisotropy (FA). Whole brain voxel-based analyses were conducted to compare WM between patients and controls. Regional WM was correlated with the number of incorrect responses across all participants. Patients made more emotion recognition errors than controls (p=0.02). However, patients and controls did not differ in the number of fixations made on the photograph: (p=0.21), or in the total time spent looking at the photograph: (p=0.23). Relative to controls, patients had lower FA in many voxels across the brain (all p<0.05). Across all participants, FA was negatively correlated with the number of incorrect responses in the left temporal region (r=-0.503, p=0.005). Patients treated for brain tumors display emotion recognition deficits and WM damage. The emotion recognition deficits do not appear to result from inattention to the photographs. Our results suggest that left temporal WM may be important for successful emotion recognition.
DIPG-36. ANTI-GD2 CHIMERIC ANTIGEN RECEPTOR T CELLS AS A POTENT IMMUNOTHERAPY REGIMEN IN XENOGRAFT MODELS OF HISTONE 3 K27M MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Christopher Mount, Robbie Majzner, Shree Sundaresh, Evan Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Pamelyn Woo, Skyler Rietberg, Hannes Vogel, Michelle Monje, Crystal Mackall
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) and other histone H3 K27M (H3K27M) mutated diffuse midline gliomas (DMGs) are aggressive and universally fatal pediatric brain cancers. Chimeric antigen receptor (CAR)-expressing T-cells have mediated impressive clinical activity in B-cell malignancies, and recent results suggest benefit in CNS malignancies. Here, we report that patient-derived H3K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T-cells incorporating a 4-1BBz costimulatory domain demonstrated robust antigen-dependent cytokine generation and DMG cell killing in vitro. In five independent patient-derived H3K27M+ DMG orthotopic xenograft models, systemic administration of GD2-CAR T-cells cleared engrafted tumors, save a small number of residual GD2-low glioma cells. Using a fluorescently-labeled GD2-CAR, we demonstrate tumoricidal GD2-CAR T cells infiltrating the brain parenchyma and sparing of local neurons during tumor clearing. While GD2-CAR T-cell administration was tolerated in the majority of animals, peri-tumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Similar swelling in thalamic xenograft models is lethal in a significant fraction of animals, presumably due to third ventricular compression and lethal transtentorial herniation. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-CAR T-cell therapy for H3K27M+ diffuse gliomas of the pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
Biomarkers of oxidative stress in patient with colorectal cancer
Authors: H. Haddouche
Journal: Annals of Oncology (2018)

Introduction: The number of colorectal cancer increases regularly every year in Algeria and precisely in Tlemcen. It is a disease involving several genetic, hormonal, professional, environmental, but also behavioral factors, namely nutrition, the objective is to evaluate the nutritional and lipid profile on the one hand and some oxidative parameters of and to determine the relationship that may exist between nutritional factors and oxidative stress in patients with this type of cancer. Methods: Thirty-three patients with newly diagnosed colorectal cancer were recruited from the Department of Gastroenterology, C.H.U. (CL, HDL-LC, LDL-CL, TG) and the oxidative status (ORAC, Catalase, Vitamin C, MDA) of Tlemcen and thirty-five healthy controls. Results: A very significant difference was observed for patients with liver cancer compared to ORAC controls (1, 143 ± 0.121) (0, 4197 ± 0.0456) p < 0.000; MDA (0, 2400 ± 0.0492) (0, 083 ± 0.0275) P < 0.008; Catalase (1.385 ± 0.162) (0, 588 ± 0.219) p < 0.008; LDL-CHOL (0.4300 ± 0.0239) (1. 0692 ± 0.0627 p < 0.000, on the other hand no difference was observed for Vitamin C (0.221 ± 0.0465) (0, 1947 ± 0.0889) p < 0.615 HDL-CHOL (0.4300 ± 0.0322) (0.466 ± 0.031) p < 0.355 Conclusion: The balance of the oxidizing/antioxidant status is a primary factor in oncology. The free radicals can lead to the appearance of mutations and, conversely. Oxidative stress, colorectal cancer.
Association between duration of oxaliplatin-free interval and effect of reintroduction of oxaliplatin-containing chemotherapy in patients with metastatic colorectal cancer (mCRC)
Authors: M. Fedyanin, A. Tryakin, A. Bulanov, A. Popova, E. Ignatova, O. Sekhina, D. Chekini, E. Polyanskaya, H. Elsnukaeva, I. Pokataev, S. Tjulandin
Journal: Annals of Oncology (2018)

Introduction: Reintroduction of chemotherapy and targeted agents is one of the suitable treatment options in patients with mCRC after 3rd line of therapy. The aim of this study was to evaluate association between duration of oxaliplatin-free interval and effect of reintroduction of oxaliplatin-containing chemotherapy. Methods: Patients who received oxaliplatin-containing regimen (FOLFOX, XELOX, FLOX) at least in two lines were included in the study. Only 47 of 430 (10.9%) patients met the inclusion criteria. The mean age was 58 (min 38 max 81, σ = 9.3), male – 40.4%, right sided tumor was revealed in 29.8%, primary tumor was resected in 91.5% of cases, metastasectomy was performed in 38.3%. The main primary endpoints were progression free survival (PFS) and overall survival (OS). A two-sided significance test with a P value of less than 0.05 was considered significant. Statistical analyses were performed using Statistical Package for the Social Sciences Version 22.0 (SPSS Inc., Chicago, IL). Results: Reintroduction of oxaliplatin was performed more often in 3rd line, after 1st line oxaliplatin-containing chemotherapy – in 20 (42.6%) patients, after adjuvant chemotherapy – in 4 (8.5%), after 2nd line – in 1 patient. Also, oxaliplatin was administered in the 1st line after adjuvant oxaliplatin-containing chemotherapy in 12 (25.5%) patients, in 2nd line after 1st line or after adjuvant oxaliplatin-containing chemotherapy - in 8 (17%) and 2 (4.3%) of patients, respectively. Median PFS for patients with oxaliplatin-free interval < 6 months (n = 25) was 3 months, 7-23 months (n = 13) – 5 months and ≥ 24 months (n = 9) – 6 months (HR 0.76, 95%CI 0.5-1.0, p = 0.1). Median OS for patients with oxaliplatin-free interval <6 months was 5 months, 7-23 months - 12 months and ≥24 months - 24 months (HR 0.64, 95%CI 0.4-0.9, p = 0.04). Conclusion: The clinical and statistical significant effect of reintroduction of oxaliplatin-containing chemotherapy on progression free and overall survival was achieved only if the duration of oxaliplatin-free interval was more than 6 months.
MBRS-22. EZH2 OVEREXPRESSION INCREASES THE ONCOGENIC CHARACTER OF CEREBELLAR PROGENITORS AND ISOGRAFTS IN MICE RESULT IN TUMORS RESEMBLING GROUP 3 MEDULLOBLASTOMA
Authors: Ismail Sola, Sujatha Venkataraman, Angela Pierce, Ilango Balakrishnan, Diane Birks, Nicholas K Foreman, Rajeev Vibhakar
Journal: Neuro-Oncology (2018)

Previous studies have shown that EZH2, an epigenetic developmental regulator, is overexpressed in medulloblastoma. EZH2 is known to repress developmental genes in embryonic stem cells to maintain their stem cell characteristics. To identify the transcriptional networks that may be driving medulloblastoma oncogenesis, we overexpressed EZH2 (EZH2Ox) in the C17.2 cerebellar progenitor immortalized cell line. In addition, to understand the effects of EZH2 loss of function on transcriptional networks we deleted the catalytic methyltransferase SET domain of EZH2 (EZH2ΔS). Comparing RNA-seq data of the control C17.2, EZH2Ox, and EZH2ΔS cell line using Gene Set Enrichment Analysis (GSEA) showed that the oncogenic character of EZH2Ox cells was significantly increased. EZH2 overexpression triggered oncogenic pathways including inhibition of neural differentiation. Soft Agar, colony formation, and neurosphere size assays all indicated an increase in the tumorigenic potential of EZH2Ox cells. The results of our RNA-seq analysis and in vitro oncogenic assays suggest that EZH2 overexpression in the C17.2 cerebellar progenitors are likely to be tumorigenic therefore we isografted EZH2Ox cells and the control cells into the cerebellum of athymic nude mice. Four of the six mice with EZH2Ox cell isografts grew cerebellar tumors while none of the control mice had tumor growth. Pathology indicated the tumorous cells were large cell anaplastic consistent with group 3 medulloblastoma. Our results suggest that EZH2 is a candidate oncogenic driver in medulloblastoma.
Can Macula and Optic Nerve Head Parameters Detect Glaucoma Progression in Eyes with Advanced Circumpapillary Retinal Nerve Fiber Layer Damage?
Authors: Fabio Lavinsky, Mengfei Wu, Joel S. Schuman, Katie A. Lucy, Mengling Liu, Youngseok Song, Julia Fallon, Maria de Los Angeles Ramos Cadena, Hiroshi Ishikawa, Gadi Wollstein
Journal: Ophthalmology (2018)
IMMU-07. IMMUNOGENIC CELL DEATH DURING MAINTENANCE CHEMOTHERAPY AND SUBSEQUENT MULTIMODAL IMMUNOTHERAPY FOR GBM
Authors: Stefaan Van Gool, Jennifer Makalowski, Volker Schirrmacher, Wilfried Stuecker
Journal: Neuro-Oncology (2018)

In a retrospective analysis of 56 patients with primary GBM treated with multimodal immunotherapy as part of their first line treatment in a personalized treatment setting, we detected 20 patients in whom Newcastle Disease Virus (NDV) and modulated electrohyperthermia (mEHT) were added at days 8/9/10 during TMZ maintenance (TMZm) cycles, multimodal NDV/mEHT/DC vaccinations were administered after TMZm, and further NDV/mEHT treatments were given thereafter. Median age was 57.5 years (ranging 17 till 67y, one 7-year old child with gliosarcoma). KPI was >70 (50 for one 17-year old patient). Patients were treated with a median of 27 (14-115) NDV infusions, 24 (4-117) mEHT sessions and 2 (0-13) DC vaccinations. Median OS was 25 months with a 3-year long-term OS of 50% (CI95% +26%, -32%). There were no major toxicities for this ambulatory treatment. The group was further divided into subgroup 1: 12 patients adding NDV/mEHT immediately after radiochemotherapy; and subgroup 2: 8 patients adding NDV/mEHT later-on during TMZm cycles. Patient characteristics were equal, as were DC vaccinations, while more NDV/mEHT were administered in subgroup 1. The median OS was 37 versus 24 months (p=0.00119) for subgroup 1 resp. 2. The data suggest that addition of immunogeneic cell death (ICD) via NDV/mEHT early during TMZm might be beneficial in controlling disease progression. While TMZm only targets dividing tumor cells, most when MGMT is methylated, ICD via NDV and mEHT targets both dividing but also non-dividing tumor cells.
DIPG-70. CLINICAL, RADIOLOGICAL, PATHOLOGICAL AND MOLECULAR CHARACTERISTICS OF CHILDREN &lt;3 YEARS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Allison Bartlett, Anne Cochrane, Adam Lane, Nancy Yanez-Escorza, Brooklyn Chaney, Renee Doughman, Mariko DeWire-Schottmiller, Stewart Goldman, Kathy Warren, Pratiti Bandopadhayay, Nicholas Foreman, Chie-Schin Shih, Jane Minturn, Ute Bartels, Roger Packer, Javad Nazarian, Tim Hassall, Yvan Samson, Michelle Monje-Deisseroth, Paul Fisher, Lars Wagner, Carl Koschmann, David Ziegler, Mark Kieran, Cynthia Hawkins, Peter White, Phillip Dexheimer, Jacob Hendershot, Rachid Drissi, Christine Fuller, James Leach, Blaise Jones, Maryam Fouladi
Journal: Neuro-Oncology (2018)

Children <3 years with DIPG are reported to have a higher rate of long-term survival (LTS, overall survival (OS) ≥24 months). In patients <3 years with centrally confirmed DIPG, we compared clinical, radiological, histological and molecular characteristics between LTS versus short-term survivors (STS <24 months). Data from children <3 years on the International DIPG Registry (IDIPGR) were analyzed. Among 782 DIPG patients, 53 were <3 years; 13 were excluded (3 without imaging, 10 “unlikely DIPG” on central review). Of the remaining 39 with at least 24-month follow-up, 10 (26%) were LTS. Among 29 patients who received therapy, 9 (31%) were LTS; median OS was 16 months (range: 2–123+ months); 27/29 (93%) received radiotherapy, including all treated LTS (9/9). Median OS among patients who did not receive therapy was 2 months, but included one LTS (37 months). LTS presented with longer symptom duration (p=0.004); tumor size, ring enhancement, necrosis and extra-pontine extension on MRI did not reach significance. Biopsy and/or autopsy was performed in 43% of patients; 50% had H3K27 mutations. Whole genome sequencing and RNA sequencing are being conducted to correlate key parameters (e.g. NTRK fusions, P53 mutations, H3K27 mutations, ACVR1) with outcome. In the largest series reported to date, children <3 years with centrally confirmed DIPG demonstrated a significantly higher rate of LTS and improved median OS. LTS were more likely to have longer duration of symptoms. Only 50% had H3K27 mutations. Final genomic analyses will be presented, and may reveal predictors of improved outcome.
MBCL-21. EARLY CHILDHOOD MEDULLOBLASTOMA: SUBGROUP-SPECIFIC SURVIVAL IN PATIENTS TREATED WITH SYSTEMIC CHEMOTHERAPY AND INTRAVENTRICULAR MTX TO AVOID CRANIOSPINAL RADIOTHERAPY
Authors: Martin Mynarek, Marcel Kool, Ulrich Schueller, Katja von Hoff, Tanvi Sharma, Vasilisa Rudneva, Torsten Pietsch, Paul Northcott, B -Ole Juhnke, Barbara Meissner, Monica Warmuth-Metz, Rolf D Kortmann, Giles Robinson, Andreas von Deimling, Stefan Pfister, Stefan Rutkowski
Journal: Neuro-Oncology (2018)

Methylation-based tumor classification results were obtained from 86 patients younger than four years with medulloblastoma treated with systemic chemotherapy and intraventricular methotrexate to avoid craniospinal radiotherapy (CSI). 70 were HIT trial participants and 16 observational patients. Subgroup specific survival was analyzed. Median follow-up was 8.3 years in the 61 patients alive at last follow-up. 33 patients presented with metastatic disease. Methylation profiling results were WNT (n=1), SHH_INF (n=43), Group 3 (GRP3; n=32) and Group 4 (GRP4; n=10). Of 39 patients with desmoplastic/nodular histology, 38 patients had SHH_INF, one GRP4 medulloblastoma. Survival differed significantly according to methylation subgroup (5y-PFS WNT: 0%, SHH_INF: 79%, GRP3: 31%, GRP4: 70%, p<0.001; 5y-OS: WNT 100%, SHH_INF: 95%, GRP3: 43%, GRP4: 100%, p<0.001). Within the SHH_INF subgroup, no additional risk factors were identified (SHH-I [n=23] vs. SHH-II [n=20; p=0.767(PFS)/0.177(OS)], chromosome 2 gain [n=10; p=0.123(PFS)/0.430(OS)], chromosome 9q loss [n=16; p=0.904(PFS)/0.224(OS)]). In GRP3 medulloblastoma, neither MYC-amplification (n=11, p=0.172[PFS]/0.064[OS]) nor metastatic disease (n=17; p=0.710[PFS]/0.971[OS]) predicted survival. 5-year radiotherapy free survival (CSI or local RT) was WNT: 0%, SHH_INF: 81%, GRP3: 6% and GRP4: 40%; p<0.001. In contrast to previously reported poor outcomes in patients with SHH-infant medulloblastoma subgroup SHH-I when treated with systemic chemotherapy alone, chemotherapy with intraventricular methotrexate was effective and avoided CSI in both SHH infant subgroups. The role of intraventricular MTX in this context needs further evaluation. Outcome for GRP3 medulloblastoma was poor, independent of other risk factors. Patients with GRP3 or GRP4 medulloblastoma frequently received radiotherapy for relapsing or non-responsive disease.
DIPG-23. BRAINSTEM RADIATION EXPOSURE CONFERS SUBSTANTIAL RISK OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) IN MEDULLOBLASTOMA SURVIVORS: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
Authors: Hunter Gits, Maia Anderson, Becky Zon, Christopher Howell, Katayoon Kasaian, Tingting Qin, Stefanie Stallard, Daniel Polan, Martha Matuszak, Marcia Leonard, Drew Pratt, Daniel Spratt, Siriam Venneti, Rajen Mody, James Leach, Blaise Jones, Christine Fuller, Sarah Leary, Ute Bartels, Eric Bouffet, Torunn Yock, Patricia Robertson, Maryam Fouladi, Nicholas Gottardo, Carl Koschmann
Journal: Neuro-Oncology (2018)

With improved survivorship in medulloblastoma, there has been increasing recognition of the occurrence of secondary malignant brain tumors. To date, no studies have specifically addressed the risk of diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. We queried the International DIPG Registry and identified six cases of DIPG with prior medulloblastoma. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials. Incidence of DIPG after medulloblastoma ranged from 0.3–3.9%. All 12 cases underwent surgical resection followed by craniospinal photon irradiation (range 18–36 Gy) and posterior fossa boost (range 19.8–36 Gy). Posterior fossa exposure was greater than 53 Gy in all cases. Median time to diagnosis of secondary DIPG was 7 years (range 2–11 years). Patients died of secondary DIPG a median of 8 months after diagnosis (range 4–17 months). Molecular subgroup of primary medulloblastomas with available tissue (n=5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). Tumor/germline exome sequencing of three secondary DIPGs demonstrated tumors to be H3.3 wildtype and harbor higher mutational burden than radiation-naïve DIPGs. Mutational signature analysis of secondary DIPGs showed mutations consistent with radiation-induced DNA damage (e.g., insertional event in TP53), as well as mutations in other oncogenic drivers (e.g., NRAS, PI3KCA), suggestive of distinct mutational processes compared with primary DIPGs. In conclusion, we report for the first time that survivors of pediatric medulloblastoma are at risk for the development of secondary DIPG, likely consequent to radiation exposure. This risk highlights the importance of radiation field, volume, and modality in medulloblastoma treatment.
Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine
Authors: Manendra Babu Lankadasari, Jayasekharan S. Aparna, Sabira Mohammed, Shirley James, Kazunori Aoki, Valsalakumari S. Binu, Sindhu Nair, Kuzhuvelil B. Harikumar
Journal: Theranostics (2018)

Rationale: Pancreatic cancer is associated with poor prognosis with a 5-year survival rate of less than 6%.Approximately 90% of pancreatic cancer patients harbor somatic mutations in the KRAS gene.Multiple lines of evidence suggest a persistent activation of STAT3 in KRAS-driven oncogenesis contributing to desmoplasia and gemcitabine resistance.Sphingosine 1-phosphate receptor 1 (S1PR1) is an integral component of tumor progression and maintains an activated state of STAT3.FTY720 is an approved drug for multiple sclerosis and acts as a functional antagonist for S1PR1.Here we explored the potential utility of FTY720 to target S1PR1/STAT3 and other major signaling pathways in pancreatic cancer, and sought proof-of-principle for repurposing FTY720 for the treatment of pancreatic cancer.Methods: We examined the activity of FTY720 in the proliferation, apoptosis, and cell cycle assays in human and mouse pancreatic cancer model systems.Further, we studied the efficacy of using a combination of FTY720 and gemcitabine as opposed to individual agents in vitro as well as in vivo Results: Treatment of human and mouse pancreatic cancer cells with FTY720 resulted in inhibition of growth, increased apoptosis, and cell cycle arrest.FTY720 in combination with gemcitabine breached the mitochondrial membrane potential, altered the S1PR1-STAT3 loop, and inhibited epithelial to mesenchymal (EMT) transition.Data from murine models exhibited a marked reduction in the tumor size, increased apoptosis, inhibited NF-κB, S1PR1/STAT3, Shh signaling and desmoplasia, modulated the expression of gemcitabine-metabolizing transport enzymes, and restored the expression of tumor suppressor gene PP2A.Conclusion: Taken together, our results established FTY720 as a propitious molecule, which increases the efficacy of gemcitabine and represents a promising agent in the management of pancreatic cancer.