tbuckley/cabot-search huggingface dataset:
RTHP-16. RADIATION INDUCED SIGNAL CHANGES ON MAGNETIC RESONANCE IMAGING IN ADULT PATIENTS WITH BRAIN TUMORS TREATED WITH PENCIL BEAM SCANNING PROTON THERAPY
Authors: Warissara Rongthong, Nadia Laack, Chris Beltran, Hok seum Wan Chan Tseung, Kristofer Roberts, Sujay Vora, Anita Mahajan
Journal: Neuro-Oncology (2018)

OBJECTIVES: We report radiation induced signal changes (RIC) on MRI in adult patients with brain tumors treated with pencil beam scanning proton therapy (PBS-PRT). All patients > 18 years receiving standard fractionation RT (4554 GyE) for a primary brain tumor with > 6 month follow-up were included. Post-RT MRIs were compared to the pre-RT scans. RIC was defined as new contrast enhancement (CET1W) and/or T2-FLAIR (T2W) changes MRI outside the GTV (CTCAE v4.0 grading was used). Monte Carlo, RBE (relative biologic effectiveness), and LET plan evaluation pre-RT were performed. Tumor, clinical and treatment factors were analyzed. Twenty-one patients were identified. RIC developed in 17/21 (81%: 2 CET1W, 15 T2W). All RIC appeared adjacent to surgical cavity and/or GTV in areas of increased RBE. 3 patients developed symptomatic RIC: All three patients had CET1W changes within tumor. Patient 1 received 50.4 GyE for a subtotally resected skull base meningioma. T2W changes developed at 3 months and CET1W changes in the tumor appeared at 7 months. Grade 2 symptoms (headache, unsteadiness, incontinence) developed by 14 months. Symptoms and imaging improved with dexamethasone taper by 22 months. Patient 2 received 54GyE for a subtotally resected grade II oligoastrocytoma. 4 months post-RT patient developed perilesional T2W. Headaches developed at 7 months and resolved following dexamethasone taper. Patient 3 received 54GyE for a progressive tectal plate glioma. At 2 months post-RT, CET1W changes within the tumor and T2W perilesional changes developed. Grade 3 diplopia developed a month later. The CET1W and T2W changes resolved at 13 months. No relationships between factors and RIC were identified. Asymptomatic RIC are common after RT, but symptoms are infrequent. Symptoms appear to be associated with post-PRT changes within tumor. A larger cohort including comparison to photon treatments and RBE will be evaluated in the future.
NCOG-02. LONGITUDINAL AND PROSPECTIVE NEUROBEHAVIORAL OUTCOMES IN NEWLY-DIAGNOSED PRIMARY CNS LYMPHOMA PATIENTS TREATED WITH PRIMARY CRANIAL RADIOTHERAPY COMBINED WITH OR WITHOUT MTX-BASED CHEMOTHERAPY
Authors: Shinn-Yn Lin, Chi-Cheng Yang, Ping-Ching Pai, Yu-Jen Lu, Yin-Cheng Huang, Chi-Cheng Chuang
Journal: Neuro-Oncology (2018)

tus.RESULTS: We found that ADAMTSL4 was enriched in GBM, IDH wild-type and MGMT methylated groups.According to the TCGA classification scheme, ADAMTSL4 can act as a potential marker for malignant subtypes.Bioinformatical analyses revealed that ADAMTSL4 was significantly correlated to the immune processes in GBM, especially representing the infiltration of immune cells and complicated tumor microenvironment.Clinically, high expression of ADAMTSL4 was an independent indicator of poorer prognosis.CONCLUSION: The expression of ADAMTSL4 is closely related to the clinicopathologic characteristics of pGBM.Meanwhile, it plays a significantly predictive role in immune processes.For its characteristic of secreted glycoprotein, ADAMTSL4 is a promising circulating biomarker for pGBM, deserving further investigation.
Resolution of sickle cell disease–associated inflammation and tissue damage with 17R-resolvin D1
Authors: Alessandro Matte, Antonio Recchiuti, Enrica Federti, Bérengère Koehl, Thomas Mintz, Wassim El Nemer, Pierre-Louis Tharaux, Valentine Brousse, Immacolata Andolfo, Alessia Lamolinara, Olga Weinberg, Angela Siciliano, Paul C. Norris, Ian R. Riley, Achille Iolascon, Charles N. Serhan, Carlo Brugnara, Lucia De Franceschi
Journal: Blood (2018)
RARE-16. CLINICAL AND HISTOPATHOLOGICAL CHARACTERISTICS OF YOUNG ADULTS WITH GLIOBLASTOMA AT DIAGNOSIS
Authors: Zachary Vaslow, John Kirkpatrick, Mary Affronti, Patrick Healy, James Herndon, Eric Lipp, Leslie Thomas, Margaret Johnson, Dina Randazzo, Annick Desjardins, Henry Friedman, David Ashley, Katherine Peters
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) occurs commonly in 6th to 7th decades of life. GBM in young adults (age 18–39 yrs) is rare and the implications of this diagnosis during young adulthood has different considerations than in their older counterparts. We planned to identify young adults with GBM and to evaluate the clinical and histopathological factors in this rare group. We queried retrospectively an IRB-approved database registry from 12/2004- 10/2016. We included GBM patients by these factors: 1. Age at diagnosis as 18–39 yrs, 2. Confirmed GBM pathology at initial diagnosis, and 3. Usable information on time to first progression. We excluded patients with an initial diagnosis of WHO grades II-III glioma. We obtained available clinical and histopathological information. We estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. We found 184 young adult patients that met our criteria for inclusion in this evaluation. Median age was 33 yrs with a majority being males (n=109, 59.2%). The majority (89.1%) had surgical resection at time of diagnosis (GTR, n=106 and STR, n=58). Median OS was 41.6 mos (95% CI: 31.2, 51.6), with a 5-year OS of 38.9% (95% CI: 31.2%, 46.5%). Median PFS was 17.2 mos (95% CI: 14.1, 21). Recurrence occurred in 148 patients (80%) and 25% (n=37) were enrolled in clinical trials after 1st recurrence. While most had pathology described as GBM, there were 50 variants (27.2%) including giant cell (n=20), small cell (n=15), oligodendroglial (n=10), PNET (n=4), and rhabdoid (n=1). Known IDH1 status was 29 mutant (15.8%) and 51 wild type (27.7%) CONCLUSIONS: Diagnosis of GBM in young adults associated with a longer OS. Surgical resection at diagnosis and participation in clinical trials are common. Histopathology for this group can be heterogeneous. Providers should tailor treatment and survivorship planning uniquely to the young adult GBM population.
Abstract 15392: Inflammation and Ischemic Heart Failure: Monocyte-Mediated Cardiac Fibroblast Activation and Matrix Remodeling Through a Direct Cell-Cell Contact Mechanism
Authors: Holly E Mewhort, Brodie D Lipon, Daniyil A Svystonyuk, David G Guzzardi, Paul W Fedak
Journal: Circulation (2014)

BACKGROUND: Following myocardial infarction (MI), activated cardiac myofibroblasts facilitate extracellular matrix (ECM) remodeling to prevent mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity, however, the mechanisms are unclear. In this study, we explored the effects of peripheral blood monocytes on human cardiac fibroblast activation in a 3D ECM microenvironment. METHODS/RESULTS: Human cardiac fibroblasts isolated from surgical human heart biopsies were seeded into 3D collagen matrices. Peripheral blood monocytes isolated from healthy human donors were co-cultured with fibroblasts. Monocytes increased fibroblast activation measured by collagen ECM contraction (17.9±11.1% increase; p&lt;0.01) and resulted in local ECM remodeling observed by confocal microscopy. Under co-culture conditions that prevent cell-cell contact but allow interaction via paracrine factors, monocytes had minimal effects on fibroblast activation (6.4±7.0 vs.17.9±11.1% increase, respectively; p&lt;0.01). Multiplex analysis of the co-culture media revealed an increase in the paracrine factors Transforming Growth Factor-beta 1 (TGF-β1) and Matrix Metalloproteinase 9 when monocytes and fibroblasts were cultured under cell-cell contact conditions (162.2±11.7pg/mL and 17.5±0.5ng/mL, respectively, vs. 21.8±5.7pg/mL and 4.9 ±0.4ng/mL; p&lt;0.001). TGF-β1 blockade abolished monocyte induced cardiac fibroblast activation, as did β1-integrin. These data suggest direct cell-cell interaction between monocytes and cardiac fibroblasts through β1-integrin results in TGF-β1 release facilitating fibroblast activation and matrix remodeling. CONCLUSION: For the first time, we demonstrate that peripheral blood monocytes stimulate human cardiac fibroblast activation through a mechanism involving TGF-β1 release as a consequence of direct cell-cell interaction through β1-integrin. These data implicate inflammation as a driver of cardiac fibrosis post-MI, highlighting potential novel therapeutic targets for the treatment of ischemic HF.
EPID-19. BRAINSTEM OBESITY IN PEDIATRIC GANGLIOGLIOMA
Authors: Pournima Navalkele, Miguel Guzman, Philippe Mercier
Journal: Neuro-Oncology (2018)

Hypothalamic obesity is a well-known entity. Here we present, a case of a pediatric patient with brainstem ganglioglioma who developed rapid-onset obesity, along with relevant literature review. A 3-year-old girl presented with progressive head tilt, ophthalmoplegia, ataxia and slurry speech. MRI brain revealed locally expansile, enhancing tumor involving brainstem. MR tractography revealed tumor infiltrating corticospinal tracts. Tumor biopsy confirmed ganglioglioma WHO grade I, BRAF v600E mutated. The patient was started on a targeted chemotherapy of BRAF inhibitor vemurafenib. Body mass index (BMI) was way above 99 percentile for age with familial obesity and peri-operative use of dexamethasone contributing to it. Review of the growth chart dating back to a year before diagnosis revealed that the patient’s weight had exponentially increased from 32 to 52 pounds (95 to above 99 percentile for age), coinciding with the patient’s progressive neurological symptoms. Endocrine workup to investigate obesity did not reveal pituitary or hypothalamic dysfunction. The patient has shown a sustained clinical and radiographic response to chemotherapy 6 months post-diagnosis. Despite adherence to dietary recommendations, the patient’s weight continues to increase (60 pounds). In our patient, obesity appears to be primarily related to the brainstem tumor causing permanent disruption of circuits running between the brainstem and hypothalamus. Studies have shown that brainstem neuronal circuits (involving the nucleus of solitary tract) are sensitive to short-term energy regulation and that the central melanocortin pathway connecting neurons in brainstem and hypothalamus plays a role in regulating body weight. An adult patient with brainstem cavernoma was reported to have postoperative hyperphagia and progressive obesity possibly from injury to the hypothalamic circuits connecting brainstem to the hypothalamus. Further clinical research is warranted to validate brainstem obesity as a clinically significant entity.
Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study
Authors: Naval Daver, Guillermo Garcia-Manero, Sreyashi Basu, Prajwal C. Boddu, Mansour Alfayez, Jorge E. Cortes, Marina Konopleva, Farhad Ravandi-Kashani, Elias Jabbour, Tapan Kadia, Graciela M. Nogueras-Gonzalez, Jing Ning, Naveen Pemmaraju, Courtney D. DiNardo, Michael Andreeff, Sherry A. Pierce, Tauna Gordon, Steven M. Kornblau, Wilmer Flores, Zainab Alhamal, Carlos Bueso-Ramos, Jeffrey L. Jorgensen, Keyur P. Patel, Jorge Blando, James P. Allison, Padmanee Sharma, Hagop Kantarjian
Journal: Cancer Discovery (2018)

Abstract Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained &amp;gt;6 months. Six patients (9%) had stable disease &amp;gt;6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. Significance: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305
TMIC-20. INTERSTITIAL FLUID FLOW MAGNITUDES DRIVE CHANGES TO THE GLIOMA MICROENVIRONMENT
Authors: Kathryn Kingsmore, Caleb Stine, R Chase Cornelison, Daniel Abler, Russell Rockne, Jennifer Munson
Journal: Neuro-Oncology (2018)

Interstitial fluid flow around brain tumors is increased above normal levels. This force has been shown to drive tumor cell invasion in brain tumors and alter the extracellular matrix, vasculature, immune and cellular niches in non-nervous tissues in ways that promote tumor progression [1]. Here, by applying our dynamic contrast enhanced MRI method and analysis [2], we measured interstitial fluid flow in multiple patient cell line-derived xenograft models of glioma in mice (n=6–8 per group, four different lines). The range of interstitial velocity magnitudes is similar across these models (range from 0.1–2.6 micron/s), though intratumoral variability is high. We examined tumors by immunohistochemistry including tumor cells (proliferating cells, ki67; stem-like cells, Nestin and Sox2; apoptotic cells, Caspase 3/7), the cellular microenvironment (astrocytes, GFAP and GLAST; microglia/macrophages, Iba-1 and CX3CR1; blood vessels, CD31; neurons, NeuN and Neurofilament; oligodendrocytes, OSP1), and of the extracellular space (hyaluronan, HABP; tenascin C; white matter tracts, fluoromyelin; cytokines). Fluid flow pathways and rates are dictated by anatomical features of the brain in these models (i.e. blood vessels and white matter tracts). Blood vessel density did not significantly correlate with regions of higher velocities. Based on our observations we performed in vitro experiments in a 3D tissue engineered model of the glioma microenvironment [3] to assess invasion within the range of measured flow rates. Velocities were controlled using either microfluidic pump driven flow or pressure driven flow and cellular outcomes were assessed using flow cytometry and immunocytochemistry of the 3D gel system. The results of these studies will be discussed. 1) Munson, Shieh, Cancer Management Research (2014) 6: 317; 2) Kingsmore, Vaccari, Abler, et al. APL Bioengineering (In press); 3) Harris, Yuan, Munson, Methods (2018) 134:20–31.
NIMG-68. MRI CHANGES IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED AS PART OF A PHASE II TRIAL WITH BAVITUXIMAB, RADIATION, AND TEMOZOLOMIDE
Authors: Ina Ly, Jonathan Cardona, Andrew Beers, Ken Chang, James Brown, David Reardon, Isabel Arrillaga-Romany, Jorg Dietrich, Deborah Forst, Eudocia Lee, Justin Jordan, Lakshmi Nayak, Patrick Wen, Tracy Batchelor, Jayashree Kalpathy-Cramer, Elizabeth Gerstner
Journal: Neuro-Oncology (2018)

Glioblastoma and tumor endothelial cells express phosphatidylserine, a highly immunosuppressive membrane phospholipid. Bavituximab a chimeric monoclonal antibody binds to 2-glycoprotein 1 (2-GP1) to form a complex of 2-GP1 with phosphatidylserine, resulting in immune activation against tumor cells and anti-angiogenic effects. Phase I/II trials in other solid cancers have demonstrated response rates up to 85% when bavituximab was given with cytotoxic chemotherapy. Pre-clinical data in glioblastoma models suggested synergistic effects of phosphatidylserine blockade, radiation, and temozolomide (TMZ). In this ongoing phase II trial (NCT03139916), adult patients with IDH-wild-type newly diagnosed glioblastoma receive 6 weeks of chemoradiation, followed by 6 cycles of adjuvant TMZ (C1-C6 aTMZ). Bavituximab (3 mg/kg) is given weekly, starting week 1 of chemoradiation, for 18 weeks with the option to continue if tolerated. Physiologic MRIs are performed pre-treatment, pre-C1, pre-C3, and pre-C5 aTMZ. Within the enhancing tumor region, we measured median tumor Ktrans (reflecting vascular permeability) and relative cerebral blood volume (rCBV). Median percent changes during treatment were compared to pre-treatment values. To date, 25 of 36 anticipated patients have enrolled (10 with MGMT promoter methylation). All patients underwent pre-treatment scans. 13 have evaluable pre-C1 and 8 pre-C3 aTMZ scans. On the pre-C1 MRIs, enhancing volume decreased by 39% and median tumor Ktrans and rCBV did not change significantly. On the pre-C3 MRIs, enhancing volume decreased by 11% and Ktrans and rCBV decreased by 17% and 21%, respectively. Five patients experienced radiographic disease progression after a median of 2.6 months and 1 patient died 76 days after diagnosis due to disease progression. Bavituximab was generally well tolerated. CONCLUSIONS: Combining bavituximab with radiation and temozolomide results in decreased enhancing tumor volume, permeability, and cerebral perfusion. Continued patient accrual and imaging marker evaluation are underway to investigate the correlation between bavituximab, MRI changes, and survival.
RARE-26. MUTATIONS IN MAPK PATHWAY GENES ARE CHARACTERISTIC AND CONFIRMATORY OF MULTINODULAR AND VACUOLATING NEURONAL TUMOR OF THE CEREBRUM
Authors: Orwa Aboud, Mark Raffeld, Joseph Brown, Abraham Sabersky, Nicole Briceno, Miranda Brown, Hye-Jung Chung, Sonja Crandon, Ming Ji, Jason Levine, Snehal Patel, Jennifer Reyes, Christine Siegel, Elizabeth Vera, Liqiang Xi, Edjah Nduom, Martha Quezado, Abhik Ray-Chaudhury, Osorio Lopes, Terri Armstrong, Mark Gilbert, Brett Theeler
Journal: Neuro-Oncology (2018)

Multinodular and vacuolating neuronal tumor of the cerebrum (MVNT) is a rare, recently described neoplasm in the 2016 World Health Organization (WHO) classification with 14 cases reported to date. MVNTs usually present with epilepsy or are discovered incidentally. Median age of diagnosis is 44.9 years (22 to 71 years), and the most common location is the temporal lobe (~65%). METHODS/ After reviewing 282 patients enrolled in our natural history study between September 2016 and August 2017, we uncovered two additional cases: the first patient is a 39-year-old woman and the other is a 57-year-old man. The tumors were localized in the left temporal and left frontal lobes respectively. Gross total resection was performed in both cases. Histological features were consistent with the 2016 WHO classification and other published reports. A CNS specific molecular panel revealed a BRAF p.Leu597Arg missense mutation in our first patient, a mutation that was recently reported in one other MVNT but has not been detected in any other primary CNS neoplasm within our database. The second patients lesion was found to have MAP2K1 p.Gln56Pro missense mutation. Our literature review found 2 cases with BRAF and 5 cases with MAP2K1 mutations in MVNT. MAPK pathway alterations reported in other glioneuronal tumors include BRAF p.Val600Glu mutations as well as BRAF fusions, neither of which have been reported in MVNTs to date. CONCLUSIONS: MVNT while rare, will likely be increasingly recognized. Our results suggest that the BRAF p.Leu597Arg missense mutation, (now described in two cases) and the MAP2K1 p.Gln56Pro missense mutation, may be useful diagnostic adjuncts to histopathological features and in differentiating this entity from more commonly epilepsy associated glioneuronal tumors.
NIMG-21. SEX DIFFERENCES IN EXTREME SURVIVORSHIP AMONG PRIMARY GLIOBLASTOMA PATIENTS
Authors: Paula Whitmire, Cassandra Rickertsen, Andrea Hawkins-Daarud, Eduardo Carrasco, Julia Lorence, Gustavo De Leon, Lee Curtin, Spencer Bayless, Kamala Clark-Swanson, Noah Peeri, Christina Corpuz, Christine Paula Lewis-de Los Angeles, Bernard Bendok, Luis Gonzalez-Cuyar, Sujay Vora, Maciej Mrugala, Leland Hu, Lei Wang, Alyx Porter, Priya Kumthekar, Sandra Johnston, Kathleen Egan, Robert Gatenby, Peter Canoll, Joshua Rubin, Kristin Swanson
Journal: Neuro-Oncology (2018)

CNS involvement may be seen at any time point in patients with systemic Non-Hodgkin lymphoma (SNHL).The leptomeninges are the most common site of CNS involvement, however parenchymal metastases are seen in up to 1/3 of patients.Given the potentially disabling nature of such lesions, early diagnosis initiation of appropriate therapy are of paramount importance.MRI remains the primary tool for the initial detection of suspected CNS spread of systemic lymphoma.Diffusion-weighted imaging is often used employed in the diagnosis and response of cellular neoplasms.The primary goal of this study was to describe DW-Imaging characteristics in a retrospective cohort of patients with SNHL with nervous system involvement.We identified patients with SNHL and dissemination to the CNS parenchyma diagnosed at our institution between 2010 and 2018.MR data with the following sequences: T1 (with gadolinium administration), T2-FLAIR, DWI and ADC sequences were required for inclusion.Imaging characteristics such as number of lesions, location of lesions, presence of contrast-enhancement, ADC, DWI signal intensity were evaluated.Quantitative ADC analyses were performed within a target lesion, peritumoral edema, and normal white matter.Twenty-six patient fulfilled eligibility criteria.Data for quantitative analysis of ADC signal were available in 25 patients.All patients had enhancing disease.24 of 26 patients (92%) had lesions with Hyperintense DWI signal and hypointense ADC signal.One-way ANOVA analysis showed significant difference between the mean ADC Lesion, ADC peritumoral region, and ADC white matter (f-statistic 142.79 and p < 0.0001).Post-Hoc analysis showed significant difference between ADC Lesion and ADC peritumoral region, ADC pertimuoral and ADC white matter, but not between ADC lesion and ADC white matter.DW-MRI is a useful adjunct to anatomical MRI sequences in the diagnosis of CNS dissemination of SNHL.In the appropriate clinical setting, comprehensive MRI analysis may obviate the need for biopsy confirmation.