tbuckley/cabot-search huggingface dataset:
DRES-06. PREVENTING THE EMERGENCE OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA BY PARP-1 INHIBITION
Authors: Alice Yuan, Elizabeth Bering, J Gregory Cairncross, Michael Blough
Journal: Neuro-Oncology (2018)

The DNA alkylating agent temozolomide (TMZ) is active against the subset of glioblastomas (GBMs) in which the O6-methylguanine DNA methyltransferase (MGMT) gene is silenced by promoter methylation. However, despite their initial sensitivity, virtually all MGMT-methylated tumors acquire drug resistance and regrow in patients. Previously, we tested the hypothesis that inhibiting poly(ADP-ribose) polymerase-1 (PARP-1) might increase the potency of TMZ in resistant GBMs. Our results showed that primary cell lines derived from TMZ-resistant GBMs were re-sensitized by pre-treatment with the PARP-1 inhibitor ABT-888. While PARP-1 inhibitors may be useful for treating resistant cases, we predict that greater clinical benefit can be derived from its use in sensitive cases where inhibition may prevent the emergence of resistant clones. To test this hypothesis, we established an in vitro model of inducible resistance in the MGMT-methylated, TMZ-sensitive U251N GBM cell line. In this model, prolonged treatment of the U251N line with TMZ resulted in the emergence of resistant colonies of cells with de novo alterations in DNA repair pathways. Of note, sanger sequencing and western blot analyses revealed that some resistant colonies harbored mutations in mismatch repair (MMR) genes MSH2, MSH6 and MLH1 and have reduced expression of MSH2 and MSH6. These observations are strikingly similar to the recurrent, TMZ-refractory human disease where mutations in and downregulated expression of MMR genes are frequently reported. In another set of experiments, co-treatment of the parental U251N line with TMZ and ABT-888 prevents resistant colonies from emerging. Moreover, co-treatment causes established resistant colonies to regress, suggesting that PARP-1 inhibition can target and prune the evolution of TMZ-resistant populations. In summary, this work has the potential to show that PARP-1 inhibition may prevent or delay disease progression and prolong the life of patients who inherently benefit from TMZ therapy.
MNGI-15. RARE PRESENTATION OF EXTRACRANIAL PARAVERTEBRAL MENINGIOMA IN A CHILD WITH NEUROFIBROMATOSIS TYPE 2: A CASE REPORT
Authors: Sapna Oberoi, Darren Leitao, Camelia Stefanovici, Marc Del-bigio, Rick Higgins, Martin Bunge, Demitre Serleitis, Magimairajan Issai Vanan
Journal: Neuro-Oncology (2018)

Meningioma is a rare intracranial tumor of children and adolescents. Meningioma occurring outside the central nervous system is even rarer. We describe an 11- year old child who presented with extracranial paravertebral skull base meningioma and left vestibular schwannoma with an underlying neurofibromatosis type 2 (NF2). The patient presented with hearing loss, painless left neck mass and right sided horner syndrome. A CT scan and MRI revealed a skull base tumor in the region of the left carotid body encasing the vessels, opacifying the left middle ear cavity, extending intracranially through the left jugular foramen along with regional lymphadenopathy and left vestibular schwannoma. MRI spine identified Arnold-Chiari I malformation and two extramedullary enhancing lesions (1-2cms) at the level of thoracic spine. With a differential diagnosis of sarcoma and peripheral never sheath tumor with metastasis to spinal cord, partial excision of the skull-base tumor was performed along with suprahyoid neck dissection. Bone marrow examination to rule out metastasis was normal. Pathology confirmed the diagnosis of meningioma (meningothelial variant, WHO grade-1). Lymph nodes showed reactive hyperplasia. With this clinical presentation of hearing loss, extracranial meningioma, vestibular schwannoma and spinal tumour likely to be spinal meningioma or schwannoma, a diagnosis of NF2 was suspected. Next generation sequencing showed deletion of exon 4 in NF2 gene. On further screening, early changes of cataract were seen in the right eye. Surgery couldn’t be done for treatment of meningioma due to the encasement of the vital structures. Therapy with bevacizumab and everolimus was started to improve hearing loss secondary to schwannoma and extracranial meningioma. This report highlights the uncommon presentation of NF-2 and extracranial meningioma. Extracranial meningioma must be considered in the differential diagnosis in a child presenting with tumor of the skull base, middle ear and neck.
PDTM-35. GENETIC ALTERATIONS DRIVING SPINAL INTRAMEDULLARY METASTASES OF A HISTONE-MUTATED DIFFUSE MIDLINE PINEAL GLIOMA
Authors: Christopher Hong, Adam Kundishora, E Zeynep Erson Omay, Anita Huttner, Asher Marks, Michael Diluna, Kristopher Kahle
Journal: Neuro-Oncology (2018)

Diffuse midline gliomas are pediatric high-grade astrocytic gliomas with poor prognosis. The majority arise from the pons but may originate from other midline structures such as the hypothalamus, thalamus, and pineal region. While these tumors may spread along fiber tracts to local sites, metastasis is extremely rare and the genetic alterations underlying distant spread are poorly understood. A thirteen-year old male presented to us with worsening headaches, nausea, and vomiting and was found to have a pineal mass, for which biopsy showed diffuse midline glioma, WHO grade IV, harboring the H3K27M mutation. He subsequently underwent a suboccipital craniotomy for maximal resection, followed by proton beam radiation and concomitant temozolomide. One year later, he developed worsening lower extremity weakness for which MRI demonstrated bulky intramedullary tumor spread throughout his spine. He subsequently underwent tumor debulking at the cervical and lumbar levels. Pathology confirmed distant metastatic spread. Whole exome sequencing was performed for his initial pineal and recurrent spinal specimens, which demonstrated preservation of key driver mutations including FGFR1 activation mutation, loss of NF1, and the H3K27M mutation. However, there were additional gained copy number variation/loss of heterozygosity (LOH) events during recurrence including LOH of chr1q, which overlapped with the H3F3A locus resulting in increased variable allele frequency for the mutant allele and subsequent greater abundance of mutated H3F3A. Likewise, there was amplification of chr2p, an event overlapping with the oncogene MYCN. Finally, there was an increased mutation burden with increased C>T transition ratio although there was no evidence of mismatch repair gene mutations to explain the hypermutated phenotype. This is the first report of intramedullary spinal metastasis from a histone-mutated midline glioma. The underlying genetic alterations driving distant metastasis may involve MYCN oncogene activation as well as activation of a hypermutated phenotype potentially related to sequelae of enhanced mutated H3F3A activity.
Abstract 16562: Minimally Invasive Delivery of a Sustained Release Amiodorane Hydrogel to the Epicardium for Refractory Atrial Fibrillation
Authors: Rebecca D Levit, Peter F Campbell, Jose Garcia, Jonathan J Langberg, Gautam Kumar, Eric Shin, Lanfang Wang, Zemskova Marina, Andres J Garcia
Journal: Circulation (2016)

Introduction: Amiodarone is an effective medication for rhythm control in atrial fibrillation (AF) but has significant risk of toxicity in off target organs when used chronically. We developed a me...
THE ASSOCIATION OF CARDIOVASCULAR DISEASE WITH RESPIRATORY DISEASE AND IMPACT ON MORTALITY
Authors: Paul R. Carter, Jakub Lagan, Christien Fortune, Deepak L. Bhatt, Joergen Vestbo, Robert Niven, Nazia Chaudhuri, Erik Schelbert, Rahul Potluri, Christopher Miller
Journal: Journal of the American College of Cardiology (2019)
Abstract 17268: Preoperative Stroke in Infective Endocarditis - No Impact on Mortality or Timing of Surgery
Authors: Mahmoud A Diab, Gloria Faerber, Mario Walther, Anne Matz, Johannes Hedderich, Ali Hamadanchi, Torsten Doenst
Journal: Circulation (2013)

Backgroud: Infective endocarditis (IE) requiring surgery is associated with high mortality (10-36%) and the frequent occurrence of stroke is considered a significant preoperative risk factor. When ...
PDCT-08. TRACKING THE T CELL REPERTOIRE AFTER ADOPTIVE CELL THERAPY IN PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA
Authors: Oleg Yegorov, Yanina Yegorova, Anjelika Dechkovskaia, Brian Cleaver, Nathalie Clement, William Slayton, Sridharan Gururangan, Duane Mitchell
Journal: Neuro-Oncology (2018)

Adoptive cellular therapy (ACT) using transfer of tumor-specific lymphocytes is a promising way to treat tumor patients. Tumor-specific T cells can lead to tumor regression in some cancer patients who do not respond to other therapies; however, the ability to track these cells after transfer has remained limited. In this study, high-throughput deep sequencing was used to track the T cells after in vivo infusion in pediatric patients with central PNETs. Bulk peripheral blood mononuclear cells (PBMCs) are stimulated ex vivo using autologous DCs loaded with total tumor RNA. We used high-throughput T cell receptor sequencing to identify and track clones and their frequency in patients T cell isolates collected prior to adoptive cellular therapy and weekly for one month and then monthly following immunotherapy treatment. cDNA was generated with addition of a common adapter at 5 end of cDNA using RACE technology. A broad range of diversity was observed with 12772 to 33709 individual clones being identified in the different samples after ex vivo expansion. The most prevalent clone represented between 0.61 and 20% of the population depending on the patient. The patients with prolonged progression-free and overall survival maintained high frequency ex vivo expanded clonotypes for many months post infusion. We observed in these ex vivo-expanded samples significantly higher expression level of markers associated with long-lived memory T cells (CD27 and CD127) compared to short overall survival patients. In most patients, the clonal hierarchies in the ACT product did not correlate with the peak clonotype hierarchys post infusion suggesting considerable restructuring of T cell repertoire once product went in vivo. CONCLUSIONS: TCR deep sequencing can be used to quantitatively track ACT-derived T cells post infusion. Monitoring of TCR repertoire dynamics during ACT may provide an early biomarker for treatment response and clinical outcomes.
Abstract 16663: Patient and Cell Characteristics Associated With Clinical Outcomes in the CCTRN LateTIME Trial
Authors: Aruni Bhatnagar, Brian H Johnston, Jay H Traverse, Timothy D Henry, Carl J Pepine, James T Willerson, Emerson C Perin, Stephen G Eillis, David X Zhao, Dejian Lai, John P Cooke, Robert C Schutt, Barry H Trachtenberg, Micheline Resende, Ray F Ebert, Shelly L Sayre, Michelle Cohen, Michelle Cohen, Robert D Simari, Lem Moye', Christopher R Cogle, Doris A Taylor
Journal: Circulation (2014)

Background and Hypothesis: In the CCTRN LateTIME trial, there was no improvement versus placebo in cardiac function 6 months after intracoronary infusion of autologous bone marrow mononuclear cells (BMC), 2-3 weeks post-MI. We hypothesized that clinical outcomes are associated with patient demographics and BMC populations that contribute to the efficacy of the intervention. Methods: Left ventricular (LV) function was evaluated at baseline and at 6 months. BMC study product data associated with phenotype and colony formation capability were collected at baseline. Principal components analysis was used to define a composite variable, LV dysfunction, encompassing both LV volume and wall motion data. Case control analysis was then conducted comparing those with improved LV dysfunction (cases) with those without (controls). Results: Hypertension, diabetes, and obesity were associated with lower levels of endothelial progenitor cells; whereas hyperlipidemia was inversely associated with CD11b+ cells, and obesity with CD3+ cells. Adjusted multivariate analysis indicated that CD11b+ cells were negatively associated with LV function; both globally (P&lt;0.02) and regionally (P&lt;0.01 and P&lt;0.001, border and infarct zone wall motion, respectively). Global LV function was positively associated with MSC colonies formed (P&lt;0.02) and regional LV function (border zone wall motion) and with cell viability (P&lt;0.03). Case control analysis revealed a significant association of CD133+, CD34+/CD31+, and CXCR4dim cells with cases. Increased LV dysfunction was associated with CD11b+cells. Conclusions: These results suggest that CVD risk factors significantly affect BMC and that baseline BMC characteristics of individual patients may be important determinants of clinical improvement. Higher frequencies or better function of specific cell populations with endothelial, mesenchymal and migratory phenotype may predispose patients to clinical improvements, whereas higher level of CD11b+ in the BM may contribute to impaired LV function. Product selection or treatment to modify bone marrow constituents, such as negative selection of CD11b+ cells prior to BMC injection, may be a potential strategy to improve outcomes of future clinical trials.
Effect of the BTK inhibitor ibrutinib on macrophage- and γδ T cell-mediated response against Mycobacterium tuberculosis
Authors: Ana Colado, Melanie Genoula, Céline Cougoule, José L. Marín Franco, María B. Almejún, Denise Risnik, Denise Kviatcovsky, Enrique Podaza, Esteban E. Elías, Federico Fuentes, Isabelle Maridonneau-Parini, Fernando R. Bezares, Horacio Fernandez Grecco, María Cabrejo, Carolina Jancic, María del Carmen Sasiain, Mirta Giordano, Romina Gamberale, Luciana Balboa, Mercedes Borge
Journal: Blood Cancer Journal (2018)

Fil: Colado, Ana. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
The origin of neural stem cells impacts their interactions with targeted-lipid nanocapsules: Potential role of plasma membrane lipid composition and fluidity
Authors: Dario Carradori, Andreia G. dos Santos, Julien Masquelier, Adrien Paquot, Patrick Saulnier, Joël Eyer, Véronique Préat, Giulio G. Muccioli, Marie-Paule Mingeot-Leclercq, Anne des Rieux
Journal: Journal of Controlled Release (2018)
SURG-12. ANTERIOR SKULL BASE TUMOR RESECTION BY TRANSCILIARY SUPRAORBITAL KEYHOLE CRANIOTOMY
Authors: Ya-Jui Lin, Ko-Ting Chen, Pin-Yuan Chen, Kuo-Chen Wei
Journal: Neuro-Oncology (2018)

The prognosis and recurrence rate after resection of an anterior skull base lesion via transciliary supraorbital keyhole craniotomy depend on residual tumor volume. The extent to which pathology and size of tumor influence the resection rate using this approach is unknown. Sixty-two patients underwent a total of 64 operations using the supraorbital keyhole approach in this retrospective study. Meningioma was the most common tumor, followed by pituitary adenoma and craniopharyngioma. Age, sex, tumor volume, operative duration, blood loss, and complication rates were evaluated. Pre- and postoperative residual tumor volumes were measured using OsiriX software (medical image viewer system) based on magnetic resonance imaging. A 15-mL cut value divided the subjects into large versus small meningioma groups. The average resection rate for meningiomas was 95.2% compared with 83.9% for craniopharyngiomas and 53.2% for pituitary adenomas. The major complication rate (primarily blindness and hemiplegia) was 4.48% in all tumors. No operative-related deaths occurred. There were no surgical revisions to traditional large craniotomies. No significant differences in age, sex, postoperative volumes, resection rates, or recurrence rates were noted between small and large meningioma groups. However, longer operative times and hospital stays, and greater blood loss occurred in the large meningioma group. Transciliary keyhole craniotomy is a safe and effective approach for anterior skull base tumors, especially meningiomas. Excellent resection results were achieved even in cases of large meningiomas. Although longer operative times, longer hospital stays, and greater blood loss occurred in larger compared with smaller meningioma cases, recurrence rates were similar.
CADD-06. VISMODEGIB LOADED POLYOXAZOLINE (POx) MICELLES ENHANCE EFFICACY OF VISMODEGIB AND PROLONG MICE SURVIVAL, EMPHASIZE POTENTIAL OF POx MICELLES TO IMPROVE DRUG DELIVERY TO BRAIN TUMORS
Authors: Duhyeong Hwang, Chaemin Lim, Yuling Zhao, Hedi Liu, Alexander V Kabanov, Timothy Gershon, Marina Sokolsky-Papkov
Journal: Neuro-Oncology (2018)

For the roughly 30% of medulloblastoma patients with SHH-subgroup tumors, drugs that disrupt SHH signaling offer the potential of improved efficacy with reduced toxicity compared to current, non-targeted treatment. The FDA-approved SMO inhibitor vismodegib, has been shown to be safe and effective for the treatment of basal cell carcinoma. In SHH-subgroup medulloblastomas, however, initial responses to vismodegib, have been followed by resistance that develops during treatment. We hypothesized that improving the delivery of the drug across the blood-brain barrier would forestall the development of resistance. We developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and consistent, nanometer-scale particle size. We treated medulloblastoma bearing GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 (P12, P13) and then every other day. Both formulations induced an initial response. However, G-Smo mice treated with conventional vismodegib quickly progressed despite therapy. In contrast, POx-vismo-treated mice survived significantly longer than untreated mice or mice treated with conventional vismodegib. Our results show the superiority of POx-vismo and highlight the potential for POx micelles drug delivery to increase the efficacy of approved and experimental agents for brain tumor therapy. The anti-tumor effect of vismodegib, optimized in POx-vismo is significant and may, in combination with additional treatments such as radiation, lead to new treatment approaches.
Calcified nodules in retinal drusen are associated with disease progression in age-related macular degeneration
Authors: Anna C. S. Tan, Matthew G. Pilgrim, Sarah Fearn, Sergio Bertazzo, Elena Tsolaki, Alexander P. Morrell, Miaoling Li, Jeffrey D. Messinger, Rosa Dolz-Marco, Jianqin Lei, Muneeswar G. Nittala, Srinivas R. Sadda, Imre Lengyel, K. Bailey Freund, Christine A. Curcio
Journal: Science Translational Medicine (2018)

Hydroxyapatite nodules in retinal drusen may indicate risk for progression to advanced age-related macular degeneration.
Randomized Trial of Endoscopic or Open Vein-Graft Harvesting for Coronary-Artery Bypass
Authors: Marco A. Zenati, Deepak L. Bhatt, Faisal G. Bakaeen, Eileen M. Stock, Kousick Biswas, J. Michael Gaziano, Rosemary F. Kelly, Elaine E. Tseng, Jerene Bitondo, Jacquelyn A. Quin, G. Hossein Almassi, Miguel Haime, Brack Hattler, Ellen DeMatt, Alexandra Scrymgeour, Grant D. Huang
Journal: New England Journal of Medicine (2018)

The saphenous-vein graft is the most common conduit for coronary-artery bypass grafting (CABG). The influence of the vein-graft harvesting technique on long-term clinical outcomes has not been well characterized.
Abstract 12418: Fish Consumption and Adipose Tissue Content of Marine n-3 PUFA is Inversely Associated With Myocardial Infarction: A Danish Prospective Cohort Study
Authors: Anders Gammelmark, Michael S Nielsen, Christian S Bork, Søren Lundbye-Christensen, Kim Overvad, Erik B Schmidt
Journal: Circulation (2015)

Introduction: Several studies have investigated the potential benefits from marine n-3 polyunsaturated fatty acids (PUFA) on cardiovascular disease, generally suggesting a lower risk of coronary heart disease. However, recent trials have questioned these results and clinical guidelines are currently at debate. Hypothesis: This study investigated the association of fish consumption, intake of marine n-3 PUFA and adipose tissue content of marine n-3 PUFA with incident myocardial infarction (MI), expecting to find an inverse relationship. Methods: In a Danish prospective cohort study 57,053 subjects between the age of 50-64 years were enrolled from 1993-97. From national registries we identified all cases of incident MI. Dietary intake of total, fatty and lean fish was assessed using a semi-quantitative food questionnaire, and analyzed in a traditional cohort design. Adipose tissue biopsies were analyzed for all MI-cases and a randomly selected sub-cohort (n=3409). Associations between adipose tissue content of major marine n-3 PUFA and MI were examined using a nested case-cohort design. Results: During a mean follow-up time of 15.9 years, we identified 3,089 cases of incident MI. In both men and women, a high intake of fatty fish (&gt;28 g/day) was inversely related to incident MI. Comparing the highest and lowest quintile, we found a 12 % lower relative risk in men (HR=0.88; 95% CI: 0.77;1.00) and a 24% lower relative risk in women (HR=0.76; 95% CI: 0.61;0.95). Total and lean fish was neutrally associated with MI. Furthermore, high content of EPA and DHA in adipose tissue was negatively associated with incident MI. However, only EPA remained statistically significant after multivariate adjustments with a HR of 0.76 (CI: 0.59;0.98) for men and HR of 0.65 (CI: 0.45;0.94) for women. Conclusions: Incident MI was inversely associated with fatty fish intake and content of EPA in adipose tissue. This study supports the view that consumption of fatty fish may protect against MI.
Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970–99: a report from the Childhood Cancer Survivor Study cohort
Authors: Todd M Gibson, Sogol Mostoufi-Moab, Kayla L Stratton, Wendy M Leisenring, Dana Barnea, Eric J Chow, Sarah S Donaldson, Rebecca M Howell, Melissa M Hudson, Anita Mahajan, Paul C Nathan, Kirsten K Ness, Charles A Sklar, Emily S Tonorezos, Christopher B Weldon, Elizabeth M Wells, Yutaka Yasui, Gregory T Armstrong, Leslie L Robison, Kevin C Oeffinger
Journal: The Lancet Oncology (2018)