tbuckley/cabot-search huggingface dataset:
RDNA-12. ATR INHIBITOR VE-822 IS A NOVEL RADIO- SENSITIZER FOR GLIOMA
Authors: Vineshkumar Thidil Puliyappadamba, Monica Lou, Eliot Fletcher, Varun Sadaphal, Xiang Li, Ram S Mani, Bipasha Mukherjee, Sandeep Burma
Journal: Neuro-Oncology (2018)

Glioblastomas (GBM) are lethal brain tumors for which surgical resection, treatment with ionizing radiation (IR) and concurrent administration of Temozolomide (TMZ) is the mainstay of therapy. These tumors are extremely radioresistant, and resistance to radiation is one of the primary causes of therapy failure. Therefore, there is an urgent need to overcome radioresistance in GBM in order to develop effective therapies for treatment. IR induces double strand breaks (DSBs) in the DNA, and these are extremely deleterious lesions that can be repaired either by error-prone non-homologous end joining (NHEJ) or the error-free homologous recombination (HR) pathway. Our laboratory has shown that the 5’-3’ exonuclease EXO1 is crucial for DNA end resection and accurate repair pathway choice. We have previously shown that EXO1 is phosphorylated and activated by CDKs 1 and 2 in the S and G2 phases of the cell cycle which results in promotion of error-free HR as well as activation of the ATR kinase. Once activated, ATR phosphorylates EXO1 and targets it for degradation thereby preventing hyper-resection and genomic instability. Therefore, we hypothesized that ATR inhibitors could augment radiotherapy by stabilizing EXO1. Indeed, we find that that a specific ATR inhibitor - VE-822 - blocks IR-induced EXO1 degradation in a panel of GBM cell lines resulting in hyper-resection and attenuation of HR. Hence, treatment with VE-822 sensitizes GBM lines to IR in vitro. In vivo, we show that the drug can cross the blood-brain barrier and, in conjunction with IR, can block DNA repair in intracranial tumors, attenuate tumor growth and consequently extend survival of tumor-bearing mice. Our results indicate that negative regulation of EXO1 by ATR is critical for optimal DSB repair, and that this connection can be subverted by ATR inhibitors in order to improve GBM radiotherapy in the clinic.
CMET-27. OUTCOMES OF LUNG CANCER PATIENTS WITH LEPTOMENINGEAL METASTASES IN THE TARGETED THERAPY ERA
Authors: Kathryn Nevel, Aimee Cowan, Anne Reiner, Shahiba Ogilvie, Anna Skakodub, Natalie Distefano, Elena Pentsova, Adrienne Boire
Journal: Neuro-Oncology (2018)

barrier by early-generation EGFR-TKIs and evolving drug resistance.The next-generation EGFR-TKIs may have improved success in treatment of leptomeningeal metastases in non-small-cell lung adenocarcinoma when compared to the first-and second-generation EGFR-TKIs.This could be particularly true in patients with documented exon 19 deletions, as in our second case.CONCLUSION: Next-generation EGFR-TKI monotherapy could be considered in select patients with leptomeningeal metastases from lung adenocarcinoma.More research is needed to review this potential therapeutic option, especially for use as first-line therapy. CMET-25. NEOPLASTIC
PATH-26. NEURO-ONCOLOGY NEXT-GENERATION SEQUENCING 219-GENE PANEL FOR COMPREHENSIVE CLINICAL TESTING
Authors: Cristiane Ida, Emily Barr Fritcher, Christopher Zysk, Jesse Voss, Xianglin Wu, Jagadheshwar Balan, Thomas Kollmeyer, Aditya Raghunathan, Caterina Giannini, Eric Klee, Benjamin Kipp, Robert Jenkins
Journal: Neuro-Oncology (2018)

Molecular parameters were incorporated in the WHO classification of central nervous system (CNS) tumors. Despite advances in understanding the molecular biology of CNS tumors, targetable genomic abnormalities are lacking. To identify diagnostically, prognostically and potential therapeutically relevant abnormalities, we developed a next generation sequencing (NGS) assay for formalin-fixed paraffin-embedded (FFPE) tissue that evaluates 219 genes associated with adult and pediatric CNS tumors. This test consists of a DNA and an RNA subpanel for the detection of sequence alterations and gene rearrangements (known gene fusions and abnormal transcript variants, and novel fusion transcripts that contain any of the interrogated genes as a partner). The assay utilizes an amplicon-based approach with molecular barcode chemistry (to allow traceability of PCR artifacts/duplicates), Illumina sequencing and custom bioinformatics pipelines. Analytical validation included 175 samples. Overall concordance with alternative methods were 99% and 96% and success rates were 97% and 95% for the DNA and RNA subpanels, respectively. Inter and intra-assay reproducibility was 100% for both subpanels. The limit of detection (analytical sensitivity) for nucleic acid input and tumor content were 8.5 ng and 30%, and 10 ng and 10% for the DNA and RNA subpanels, respectively. The analytical specificity was high, with per base DNA sequencing false positive rate <0.4% and absent fusion transcript detection in non-neoplastic samples. We developed a robust 219-gene neuro-oncology NGS assay suitable for clinical testing of FFPE specimens, including small biopsies with low tumor content. This test, combined with chromosomal microarray analysis, detects nearly all single nucleotide variants, fusion rearrangements and copy number changes associated with CNS tumors. These tests are intended to assist in the diagnosis, prognosis and therapeutic management of adult and pediatric patients with CNS tumors, and have the potential to unravel novel genomic abnormalities and expand the understanding of the molecular biology of such tumors.
Swan, Ganz, and Their Catheter: Its Evolution Over the Past Half Century
Authors: Anjali B. Thakkar, Sukumar P. Desai
Journal: Annals of Internal Medicine (2018)

Jeremy Swan and William Ganz developed their eponymous pulmonary artery (PA) catheter in the 1970s and, in the process, revolutionized measurement of cardiac output, pressures within the left side of the heart, and resistance in systemic and pulmonary circulations. Their invention enabled diagnostic measurements at the bedside and contributed to the birth of critical care medicine; technologic advances preceding the PA catheter generally could not be used at the bedside and required patients to be stable enough to be taken to the catheterization laboratory. Swan and Ganz worked in the same department but had quite dissimilar backgrounds and personalities. This article describes their lives and careers, the state of intensive care before and after their catheter was introduced, and the natural life cycle the PA catheter faced as new, less invasive technology arrived to replace it.
ANGI-06. THE MATRIX PROTEIN THROMBOSPONDIN-1 IS A DOWNSTREAM TARGET OF TGF-β INDUCED MICROTUBE FORMATION IN GLIOBLASTOMA
Authors: Justin V. Joseph, Capucine Magaut, Amalie Trones, Julia Grosch, Wenjing Zhou, Jubayer Hossain, Md Abdul Latif, Sandra Ninzima, Frank AE Kruyt, Rolf Bjerkvig, Frank Winkler, Thomas Daubon, Hrvoje Miletic
Journal: Neuro-Oncology (2018)

Microtubes (MTs), which are cytoplasmic extensions of glioma cells, have recently been discovered as important cell communication structures. MTs are abundant in chemoresistant 1p/19q non-codeleted tumors, in particular glioblastomas, however are scarce in chemosensitive 1p/19q co-deleted oligodendrogliomas. Here we report that TGF-β is an important mediator of MT formation. TCGA data analysis revealed upregulation of TGF-β growth-factors and receptors in non-codeleted versus co-deleted tumors. TGF-β stimulation in vitro promotes enhanced MT formation in a panel of GBM stem cell lines which was blocked by a TGFBR2 inhibitor (Ly2157299). Analysis of RNA sequencing data comparing TGF-β stimulated versus unstimulated cells revealed extracellular matrix receptor interactions as a major regulated pathway. We identified Thrombospondin-1 (THBS1) as a major candidate of this pathway, which was upregulated upon TGF-β stimulation in GBM stem cell lines. Interestingly, one GBM stem cell line that did not respond to TGF-β stimulation with enhanced MT formation lacked also upregulation of THBS1. This non-responder cell line did not invade into fetal microbrains in vitro and xenografts in vivo, whereas responder cell lines showed a highly invasive and MT forming phenotype in both models. Knockdown of THBS1 in a responder cell line using shRNAs substantially reduced MT formation in vitro and in vivo. Thus, we identified THBS1 as an important mediator of MT formation downstream of TGF-β, which might play a role in therapy resistance of GBM.
Prerace medical screening and education reduce medical encounters in distance road races: SAFER VIII study in 153 208 race starters
Authors: Martin Schwellnus, Sonja Swanevelder, Wayne Derman, Mats Borjesson, Karen Schwabe, Esme Jordaan
Journal: British Journal of Sports Medicine (2018)

Objectives To examine the efficacy and feasibility of an online prerace medical screening and educational intervention programme for reducing medical complications in long-distance races. Methods This was an 8-year observational study of medical encounter rates among 153 208 Two Oceans race starters (21.1 and 56 km) in South Africa. After the first 4-year control (CON) period, we introduced an online prerace medical screening (based on European pre-exercise screening guidelines) and an automated educational intervention programme. We compared the incidence of medical encounters (per 1000 starters; all and serious life threatening) in the CON versus the 4-year intervention (INT) period. Results In comparison to the CON period (2008–2011: 65 865 starters), the INT period (2012–2015: 87 343 starters) had a significantly lower incidence (adjusted for age group, sex, race distance) of all medical encounters by 29% (CON=8.6 (7.9–9.4); INT=6.1 (5.6–6.7), p&lt;0.0001), in the 21.1 km race by 19% (CON=5.1 (4.4–5.9); INT=4.1 (3.6–4.8), p=0.0356) and in the 56 km race by 39% (CON=14.6 (13.1–16.3); INT=9.0 (7.9–10.1), p&lt;0.0001). Serious life-threatening encounters were significantly reduced by 64% (CON=0.6 (0.5–0.9); INT=0.2 (0.1–0.4); p=0.0003) (adjusted for age group and sex). Registration numbers increased in the INT period (CON=81 345; INT=106 743) and overall % race starters were similar in the CON versus INT period. Wet-bulb globe temperature was similar in the CON and INT periods. Conclusion All medical encounters and serious life-threatening encounters were significantly lower after the introduction of a prescreening and educational intervention programme, and the programme was feasible.
PDTM-16. AN IMPROVED DIFFUSE INTRINSIC PONTINE GLIOMA MODEL INITIATED IN OLIG2-EXPRESSING PROGENITORS OF THE NEONATAL BRAINSTEM
Authors: Yosuke Shimazu, Oren Becher
Journal: Neuro-Oncology (2018)

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor that arises in the pons of children. Recent studies using single cell RNAseq and enhancer analysis of DIPG tumor cells, together with analysis of the developing human pons, strongly suggest that an oligodendrocyte progenitor cell is the most likely cell-of-origin for DIPG. As there is a need for immunocompetent DIPG models that arise in the correct cell-of-origin (spatiotemporally) and recapitulates the genetic alterations of the human disease, we sought to develop a DIPG mouse model that arises in Olig2-expressing progenitors of the neonatal brainstem. Here we describe a novel mouse model by expressing PDGF-B, with H3.3K27M or H3.3 wild-type in Olig2-expressing progenitors of the neonatal brainstem using Olig2-tva-cre;p53fl/fl mice. Although both H3.3K27M tumors and H3.3 wild-type tumors have high rate of Ki-67 and Olig2 positivity, H3.3K27M tumors show a higher rate (100%) of leptomeningeal dissemination than H3.3 wild-type tumors (50%) and mice harboring H3.3K27M tumors demonstrate significantly shorter survival periods than those harboring H3.3 wild-type tumors (28 days vs. 37 days, p=0.048). Interestingly, expression of PDGF-B and H3.3K27M in Olig2-expressing progenitors of the neonatal brainstem of Olig2-tva-cre;p53fl/+ demonstrate dramatically delayed gliomagenesis relative to Olig2-tva-cre;p53fl/fl mice (28 days vs. 119 days, p<0.0001) illustrating that p53 status (heterozygous vs. homozygous deletion) impacts survival more dramatically than H3.3K27M. Ongoing studies will compare the transcriptome of H3.3K27M mutant tumors to H3.3 wild-type tumors and to human tumors harboring H3.3K27M, PDGFRA amplification and p53 mutations to further credential this model.
CMET-32. BILATERAL OCCIPITAL METASTASES: MANAGEMENT CONSIDERATIONS AND CORTICAL BLINDNESS
Authors: Mark Zaki, Saksham Gupta, Robert Mallery, Sashank Prasad, Ayal Aizer, Wenya (Linda) Bi, Ian Dunn
Journal: Neuro-Oncology (2018)

Treatment decisions for brain metastases balance potential benefits of tumor control, symptom alleviation, and survival, with the risk of functional impairment or reduced quality of life. Bilateral occipital metastases pose a risk of significant visual deficits and even cortical blindness, with an unclear rate of resolution and development of these debilitating symptoms following resection or radiotherapy. We retrospectively reviewed all cases of bilateral occipital metastases treated with surgery and/or radiotherapy between 2008–2017 at the Brigham and Women’s Hospital. 18 patients with bilateral occipital metastases (median age 64 years; 13 women, 5 men) were identified. The most frequent primary cancer sites were lung (56%), melanoma (17%) and breast (11%). Visual symptoms were present in 67% of all cases, of which 67% had a visual filed deficit, 17% had diplopia, and 17% had an acuity deficit. These metastases were initially managed with resection (44%), radiotherapy (28%), or both (28%). In patients who initially presented with visual symptoms, 75% improved with treatment while 25% remained stable. In those who presented with no visual symptoms, 67% remained at baseline, 17% worsened acutely, and 17% worsened permanently with treatment. The majority of patients were also managed with post-treatment steroids. A representative case illustration is discussed of a patient who initially received whole brain radiation therapy (WBRT) for 10 days, with dexamethasone for the first 8 days of radiation. Upon completion of WBRT, the patient developed rapidly worsening visual acuity, which subsequently improved with bilateral occipital craniotomy for tumor resection. CONCLUSIONS: Patients with bilateral occipital metastases may present with visual symptoms, including visual field loss, reduced visual acuity, and diplopia. The management of bilateral occipital metastases involves consideration of symptomatology, disease burden, and goals of care. Visual deficits frequently improve following treatment but may also develop in a minority of patients.
Endoscopic removal of dental prosthesis impacted in the duodenal papilla
Authors: Meiduo Ouzhu, Chuncheng Wu, Liansong Ye, Jigme Dawa, Bing Hu
Journal: Endoscopy (2018)

A 69-year-old man with a history of Alzheimer's disease was admitted to the emergency department 27 hours after ingesting his dental prosthesis. The patient's main complaints were dysphagia, epigastric pain, bilious vomiting, and severe nausea.
Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis
Authors: Giovanna Lucchini, Rebecca Marsh, Kimberly Gilmour, Austen Worth, Zohreh Nademi, Anupama Rao, Claire Booth, Persis Amrolia, Juliana Silva, Robert Chiesa, Robert Wynn, Kai Lehmberg, Itziar Astigarraga, Tayfun Güngör, Jan Stary, Despina Moshous, Marianne Ifversen, Daniel Zinn, Michael Jordan, Ashish Kumar, Takahiro Yasumi, Paul Veys, Kanchan Rao
Journal: Blood (2018)
SURG-21. SUPRACEREBELLAR TRANSTENTORIAL APPROACH FOR OCCIPITAL MENINGIOMA TO MAXIMIZE VISUAL PRESERVATION: TECHNICAL NOTE
Authors: Danielle Golub, Neal Mehan, Kevin Kwan, Sussan Salas, Michael Schulder
Journal: Neuro-Oncology (2018)

Surgery for resection of tentorial meningiomas that compress the primary visual cortex has a significant risk of worsening vision. This concern is especially acute in patients with a preexisting visual deficit. Approaches that involve mechanical retraction of the occipital lobe further threaten visual function. The supracerebellar transtentorial (SCTT) approach, which does not carry a risk of retraction injury, should be considered for occipital tentorial meningioma to maximize functional visual outcomes. CLINICAL PRESENTATION: A 54-year-old woman underwent two resections and radiation therapy for a right occipital oligodendroglioma as a teenager. She was left with a complete left homonymous hemianopsia. The patient now presented with progressive vision loss in her remaining right visual field. Imaging revealed a left occipital superiorly projecting tentorial meningioma. Given that preserving remaining visual function was of critical importance in this case, the SCTT approach with the patient in the prone position was chosen for resection. Traditionally favored suboccipital lateral and occipital interhemispheric supratentorial approaches risked retraction injury to visual cortex and further visual loss. A transcortical or transfalcine approach, also considered given access via the large right occipital resection cavity, would similarly require manipulation of the remaining medial rim of left occipital lobe. A Simpson grade 1 resection was achieved without disrupting the occipital lobe pia or requiring cerebellar retraction while minimizing intraoperative risk of air embolism. A diagnosis of a WHO grade II meningioma (presumably radiation induced) was made. The patients vision returned to pre-morbid baseline one week after surgery. The SCTT approach should be considered for the surgical management of patients with occipital tentorial meningiomas when visual preservation is at risk. This approach avoids transgression of visual cortex, and minimizes the risk of venous infarction or contusions from retraction injury.
PATH-33. HEXOKINASE 2 KNOCKOUT VIA CRISPR REDUCES DOWNSTREAM GENE EXPRESSION, IMPLICATING A REDUCTION IN CELL PROLIFERATION AND DRUG RESISTANCE
Authors: Daniel Blakeway, Katherine Karakoula, Mark Morris, Farjana Rowther, Kate Ashton, Tim Dawson, John Darling, Tracy Warr
Journal: Neuro-Oncology (2018)

HK2 has a prominent role in aerobic glycolysis and has been implicated in many cancer types including GBM, with overexpression associated with drug resistant phenotypes. Previously, we have demonstrated HK2 expression was upregulated between 6 to >1000 fold in GBM biopsy tissue (n=100) and patient derived cell cultures (n=13), compared to normal brain tissue. In the present study we have knocked out HK2 using CRISPR in patient-derived cultures (n=3) and the established cell line U251MG, to determine changes in the rate of cell proliferation and drug sensitivity. Additionally downstream expression changes were investigated via Qiagen profiler arrays, across 84 key genes involved in the regulation and enzymatic pathways of glucose metabolism. A substantial growth rate reduction between 38 to 44% (p<0.007) was demonstrated in CRISPR-modified cultures after 7 days compared to non-CRISPR cultures. Sensitivity to metformin was also significantly (p<0.0001) increased in response to HK2 knockout, where average ID50 values were 60% lower in cultures. Additionally CRISPR modified cultures yielded greater synergistic (CI<1) and additive effects (CI=1), with metformin and temozolomide combination treatment. Array data revealed an extensive change in downstream gene expression in CRISPR-modified cultures, between 25 to 48 genes were downregulated compared to the corresponding non-CRISPR cultures. Furthermore CRISPR-modified cultures demonstrated a similar reduction in downstream expression when compared to GBM biopsy tissue, conversely a greater number of genes had unchanged expression levels compared to normal brain tissue. This study demonstrates the predominant role of HK2 within the glycolytic pathway, with overexpression potentially key in driving the genetic alterations downstream. HK2 knockout revealed considerable ubiquitous reductions in downstream gene expression compared to GBM biopsy tissue and non-CRISPR cultures. Additionally an increase in drug sensitivity was depicted with the loss of HK2 signifying the potential of HK2 inhibition as a novel therapy in a significant subset of GBM.
“Chemocentric” chemoimmunotherapy: presensitization of tumor cells with activated CD4+ T cells synergistically enhances the cytotoxic effect of chemotherapy
Authors: Soroosh Radfar, Yixiang Wang, Hung Khong
Journal: Cancer Research (2007)

956  Background: Most patients with metastatic cancer will eventually succumb to their disease despite an initial response to chemotherapy. To enhance treatment efficacy, chemotherapy has been combined with cytokines, often with disappointing results. Another example is “Immunocentric Chemoimmunotherapy,” with primary focus placed on immunotherapy, with chemotherapy as an immunomodulator. We have developed a novel strategy termed “Chemocentric Chemoimmunotherapy,” where chemotherapy plays the central role, with immunotherapy as a chemosensitizer. The rationale is the ability of activated T cells to secret multiple cytokines, which may regulate gene expression in tumor cells. Methods: Human CD4+ T cells were isolated and activated with anti-CD3/anti-CD28 mAb. Tumor cells were presensitized with activated CD4+ T cells (aCD4), followed by treatment with various chemotherapy. Cell viability and apoptosis were determined. Transwell system was used to assess contribution of cell-cell contact vs. soluble factor(s). Results: Presensitization of A375 melanoma cells with aCD4 synergistically enhanced the cytotoxic effects of chemotherapy. Cell viability (CV) was 75% (+SD: 0.11) and 90% (+SD: 0.26) after treatment with temozolomide (TMZ) alone or with aCD4 alone, respectively. However, CV in the experimental group was 7% (+SD: 0.02). This synergistic effect was also observed with other melanoma cell lines, nonmelanoma tumor cell lines, and other chemotherapy. Two breast, one prostate, and one colon cancer cell lines were presensitized with aCD4, followed by treatment with paclitaxel, carboplatin, or 5-FU. Consistent synergistic effect was seen in each case. For example, CV in MDA-MB-231 breast cancer cells treated with paclitaxel alone or aCD4 alone was 93% (+SD: 0.16) and 52% (+SD: 0.10), respectively. However, CV in the experimental group was 8% (+SD: 0.18). The same synergism was observed in DU145 prostate cancer cell line treated with carboplatin. CV in the carboplatin-treated group and aCD4-treated group was 100% (+ SD: 0.13) and 75% (+SD: 0.14), respectively; while CV of the experimental group was 5% (+SD: 0.19). The rate of apoptosis in cells treated with both TMZ and aCD4 was 20 times higher than in cells treated with only TMZ or aCD4. This effect was due entirely to soluble factors. The aCD4 was found to secret large amounts of multiple cytokines. Preliminary data showed that IFN-γ might not be the major cytokine mediating the observed effect. Conclusion: Presensitization of tumor cells with aCD4 synergistically enhanced the cytotoxic effect of chemotherapy. This effect was completely dependent on soluble factors, most likely cytokines. We are in the process of elucidating the mechanisms underlying this dramatic synergy.