tbuckley/cabot-search huggingface dataset:
PATH-06. A NEW DIAGNOSTIC ASSAY FOR THE DETECTION OF EGFR AMPLIFICATION IN GLIOBLASTOMA TISSUE SPECIMENS
Authors: Minghao Song, Thomas Perez, Jeffrey Panella, Olga Kornfeld, Hina Amin, Frank Policht, Ekaterina Pestova, Irina Sokolova
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most common malignant brain tumor among adults with poor prognosis. Epidermal Growth Factor Receptor (EGFR) gene is found to be amplified in approximately 50% of GBM tumors. Drugs that target amplified EGFR are being evaluated in the clinical trials for the treatment of GBM patients. A new Vysis EGFR FISH (Fluorescence in situ Hybridization) assay was developed to detect amplification of the EGFR gene in glioblastoma tissue samples. The assay is comprised of two DNA probes labeled with spectrally distinct fluorophores: orange EGFR probe that hybridizes to 7p11.2-7p12 region, and green CEP 7 probe that hybridizes to a centromere of chromosome 7. Analytical sensitivity and specificity of the probes was tested on 100 metaphase spreads from 5 donors and was shown to be 100%. The assay conditions were optimized in guardbanding studies using universal reagents kits with both manual and automated VP 2000 processing methods. In feasibility study the assay demonstrated 100% (142/142) success rate for manual and 99.3% (141/142) for automated VP 2000 slide processing methods. Analytical reproducibility showed no significant differences between reviewers, slides and laboratories. The positive percent agreement for EGFR amplified specimens was 100% (480/480); negative percent agreement for non-amplified specimens was 99.8% (479/480), and overall percent agreement was 99.9% (959/960). Vysis EGFR CDx FISH Kit demonstrated high photostability, in-use stability, and real time stability for at least 19 months. Stability of FFPE tissue slides was demonstrated that allows using tissue blocks and tissue sections archived for up to 32 months without loss of performance. Fully characterized Vysis EGFR FISH assay proved to be an effective tool in detecting EGFR gene amplification in GBM FFPE tumor tissue with manual and automated assay formats. Vysis EGFR CDx FISH Kit* is being validated in the ongoing clinical trials. *In Development and not Commercially Available
CSIG-01. TUMOR TREATMENT FIELDS DOWNREGULATE SPECIFIC TRANSCRIPTION FACTORS LEADING TO REDUCED DNA REPAIR CAPACITY, INCREASED REPLICATION STRESS, THE INHIBITION OF MITOPHAGY AND ENHANCED CELL DEATH
Authors: Narasimha Karanam, Liang-hao Ding, Brock Sishc, Debabrata Saha, Michael Story
Journal: Neuro-Oncology (2017)

Tumor treating fields (TTFields) is a novel anticancer treatment modality that has revolutionized the treatment of recurrent and newly diagnosed glioblastoma. TTFields are low-intensity, intermediate frequency, alternating electric fields applied non-invasively to the skin in the region of a tumor. Our analysis of TTField exposure identified an inhibition of cell proliferation and decreased survival, though the degree of inhibition and survival varied across cell lines. Temporal gene expression changes in the presence or absence of TTFields was performed. Interestingly, we identified the down regulation of the transcription activators of the E2F transcription factor (TF) family and upregulation of the TF suppressor members of the E2F family, amongst other TFs. These changes were likely responsible for increased p53 expression, downregulated NFKB, upregulated cell cycle genes, downregulation of DNA repair genes and downregulated genes associated with proliferation. In addition, the expression of the BRCA1/FA pathway genes was significantly downregulated upon TTFields treatment. Downregulation was also seen at the protein level. DNA damage repair kinetics by quantification of g-H2AX and 53 BP1 foci showed that TTFields exposure slowed the repair of IR-induced DNA damage. We also found TTFields increased the incidence of chromatid aberrations. Using the DNA fiber assay we showed that TTFields gradually reduced replication tract lengths over time, suggesting increased replication stress. Also examined was the newly identified cytosolic role for the BRCA1/FA pathway genes, i.e., mitophagy, by hypothesizing that TTFields disrupt the clearance of damaged mitochondria which results in increased ROS production. Interestingly, electron micrographs of TTFields treated cells suggested more damaged mitochondria accumulation compared to control. We found that TTFields exposure increased ROS production suggesting a new mechanism of action for TTFields. Lastly, our data suggests that PARP inhibitors in combination with DNA damaging agents (radiation, cisplatin) and TTFields may be advantageous through the conditional vulnerability of down-regulated BRCA1.
Tobacco Product Use Among Adults — United States, 2015
Authors: Elyse Phillips, Teresa W. Wang, Corinne G. Husten, Catherine G. Corey, Benjamin J. Apelberg, Ahmed Jamal, David M. Homa, Brian A. King
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Tobacco use remains the leading cause of preventable disease and death in the United States (1).Despite declining cigarette smoking prevalence among U.S. adults, shifts in the tobacco product landscape have occurred in recent years (2,3).Previous estimates of tobacco product use among U.S. adults were obtained from the National Adult Tobacco Survey, which ended after the 2013-2014 cycle.This year, CDC and the Food and Drug Administration (FDA) assessed the most recent national estimates of tobacco product use among adults aged ≥18 years using, for the first time, data from the 2015 National Health Interview Survey (NHIS), an annual, nationally representative, in-person survey of the noninstitutionalized U.S. civilian population.
Abstract 14838: Regional Contributions to Impaired Myocardial Mechanical Function in Heart Failure With Preserved Ejection Fraction
Authors: Tor Biering-Sørensen, Maja Cikes, Elisabeth Kraigher-Krainer, Amil M Shah, Scott D Solomon, Susan Cheng
Journal: Circulation (2015)

Background: The pathophysiology underlying the transition from hypertensive heart disease (HHD) to heart failure with preserved ejection fraction (HFpEF) remains unclear. Regional differences in impaired myocardial function may contribute to the more pronounced overall mechanical dysfunction seen in HFpEF compared to HHD. Methods: We assessed regional myocardial deformation in 129 HFpEF patients, 158 hypertensive patients with HHD and no heart failure, and 40 healthy controls. Peak systolic strain was assessed in the apical 4 and 2 chamber views and the average was calculated for the 4 apical (ALS), 4 mid ventricular (MLS) and 4 basal (BLS) regions. Results: All 3 groups had preserved left ventricular ejection fraction (LVEF ≥50%). Whereas BLS and MLS were more impaired in HHD than in controls, ALS was significantly more impaired in HFPEF than HHD (Figure). In area under the receiver operating curve (AUC) analyses, ALS was the best diagnostic marker for differentiating HFpEF from HHD (AUC: ALS=0.67; MLS=0.59; BLS=0.60). After adjusting for the main characteristics that differed between HFpEF and HHD (age, e’, systolic blood pressure, NT-pro BNP, LV end-diastolic volume, and LVEF), ALS remained independently associated with HFpEF vs. HHD status (OR 1.18 [1.02-1.37], P=0.030 per 1% decrease). By contrast, global longitudinal strain was not significantly associated with HFpEF vs. HHD status in multivariable analyses (P=0.09). Conclusion: We observed that whereas basal and mid-level longitudinal strain is more impaired in HHD than in controls, apical longitudinal strain is substantially more impaired in HFPEF than HHD. These findings suggest that preservation of apical mechanical function may play an important role in the transition from HHD to HFPEF.
DRES-11. EPIGENETIC REGULATION OF TUMOR SUPPRESSOR GENE HOXD10 DURING ANTI-GLIOMA CHEMOTHERAPY
Authors: Shivani Baisiwala, Cheol Park, Fatemeh Atashi, Seamus Caragher, Anne Christensen, Miranda Saathoff, Jack Shireman, Atique Ahmed
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM), the most common primary brain tumor, is highly lethal despite the use of radiation and temozolamide-based (TMZ) chemotherapy. Even with therapy, median survival for patients remains approximately 15 months following diagnosis. While current treatments are effective in treating primary tumors, recurrent tumors are nearly universally fatal due to their increased aggressiveness and therapeutic resistance. Our understanding of the processes governing recurrence remains incomplete. GBM cells alter gene expression by epigenetic changes in response to therapy. These changes are thought to participate in generating recurrence. Here, we use genome-wide chromatin immunoprecipitation (ChIP) in parallel with DNA sequencing analyses (ChIP-seq) to show that EZH2, a powerful epigenetic regulator of histone methylation, preferentially binds to the homeobox D10 (HOXD10) promoter region following treatment with TMZ. This binding reduces the transcription and the protein level of HOXD10, an established tumor suppressor known to influence cell proliferation and invasion. Decreased HOXD10 expression correlates with elevated levels of MMP14 and MMP9, two well-established players in cancer cell invasion and motility. Thus, we propose that treatment with TMZ induces specific changes in EZH2 binding, which in turn elevates expression of MMP14 (2.8 fold increased p=0.007) and MMP9 (3 fold increased p=0.02) to enhance the invasive potential of GBM. This epigenetic process may underlie the genesis of recurrent GBM tumors. Our work demonstrates a novel interaction between EZH2 and HOXD10 and further highlights the importance of epigenetics in GBM recurrence.
P2.02-012 The Epigenetic Role of LSD1+8a in Small Cell Lung Cancer
Authors: A. Wirawan, K. Tajima, F. Takahashi, M. Hidayat, R. Kanemaru, Y. Koinuma, D. Hayakawa, M. Tajima, N. Matsumoto, K. Kanamori, I. Takeda, M. Kato, I. Kobayashi, N. Shimada, K. Takahashi
Journal: Journal of Thoracic Oncology (2017)
Mouse model of CCl4-induced HCC: histopathological changes and expression of EGF and CD133
Authors: Tsutomu Fujii, Bryan Fuchs, Gregory Lauwers, Yakup Kulu, Michael Lanuti, Kenneth Tanabe
Journal: Cancer Research (2008)

2954   Background: Repeated exposure to carbon tetrachloride (CCl4) has historically been used as a model of chronic liver injury leading to cirrhosis and hepatocellular carcinoma (HCC) in rodents. Chronic liver injury leads to hepatic stellate cell (HSC) proliferation and differentiation and consequent deposition of extracellular matrix proteins like collagen resulting in fibrosis and cirrhosis. A novel subpopulation of HSCs, which express CD133 and exhibit properties of progenitor cells, has recently been described in rats. In the setting of chronic human liver injury, epidermal growth factor (EGF) and EGF receptor (EGFR) have been proposed to have vital roles in liver regeneration and tumor progression. Methods: Strain A/J male mice were treated 3X a week for 17 weeks by oral gavage with either 0.04 cc of a 40% solution of CCl4 in olive oil or vehicle. Pathological examination of the livers was performed with Masson9s trichrome and HE however, no evidence of cirrhosis was present. Consistent with this, increased expression of desmin and GFAP, known to be representative markers of HSCs, was observed. Interestingly, CD133 was dramatically up-regulated after treatment with CCl4 and was attributed to HSCs as the expression of VEGFR2, a marker for endothelial progenitor cells, was not altered. Further, upon withdrawal of CCl4, the expression of CD133 returned to control levels in the surrounding normal tissue but remained elevated in the tumor. Finally, EGF and EGFR expression significantly decreased during chronic liver injury, but returned to nearly control levels during liver repair after withdrawal of CCl4. Conclusions: The use of CCl4-induced chronic liver injury in mice may not be an adequate model of human cirrhosis. In this study, no evidence of cirrhosis was seen and HCCs developed within a setting of fibrosis and not cirrhosis as typically observed in humans. Further, EGF and EGFR expression decreased during chronic liver injury. These results suggest that species-specific differences exist with respect to the histopathological and molecular pathogenesis of chronic liver disease. The dramatic up-regulation of CD133 is a notable finding and the contribution of CD133+ HSC to liver regeneration and tumor progression await further studies in rodents and humans.
Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors
Authors: C. Albany, N. Adra, A.C. Snavely, C. Cary, T.A. Masterson, R.S. Foster, K. Kesler, T.M. Ulbright, L. Cheng, M. Chovanec, F. Taza, K. Ku, M.J. Brames, N.H. Hanna, L.H. Einhorn
Journal: Annals of Oncology (2017)

BackgroundTo report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program.Patients and methodsWe conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan–Meier method was used to estimate PFS and OS.ResultsWith a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001.ConclusionThe MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.
P2.14-020 Clinical Validation of NTCP-Models for Esophagus Toxicity in Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiation
Authors: I. Walraven, M. Kwint, S. Marshall, M. Verheij, J. Belderbos, T. Janssen
Journal: Journal of Thoracic Oncology (2017)
PDCT-02. EVALUATION OF DEPATUXIZUMAB MAFODOTIN (ABT-414) IN CHILDREN WITH HIGH GRADE GLIOMA (HGG) AND DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Martin van den Bent, Birgit Geoerger, Vassilis Golfinopoulos, Peter J Ansell, Earle Bain, Jim Looman, Hao Xiong, JuDee Fischer, Kyle D Holen, Darren Hargrave
Journal: Neuro-Oncology (2017)

Pediatric HGGs (WHO grade III and IV gliomas) and DIPGs have no adequate therapy and are almost universally fatal. Depatuxizumab mafodotin (depatux-m), formerly called ABT-414, is an antibody-drug conjugate, comprised of an anti-EGFR antibody linked to a microtubule cytotoxin, monomethyl auristatin F (MMAF), that has demonstrated promising antitumor activity in patients with epidermal growth factor receptor (EGFR) gene-amplified tumours in a phase 1 study in adult GBM (M12-356, NCT01800695). While EGFR amplification occurs in about 50% of GBM (WHO grade IV glioma), it occurs in up to 3% only in children with HGG. Due to the rarity of pediatric HGG with EGFR amplification, a nested cohort has been designed within a phase 2 study of depatux-m in adult patients with EGFR amplified, recurrent GBM (INTELLANCE 2, NCT02343406). ≥6 HGG or DIPG patients will be enrolled globally without randomization to receive depatux-m in this nested pediatric cohort. Eligible patients will be 3-17 years of age, with recurrent pediatric HGG or DIPG exhibiting EGFR amplification or EGFRvIII mutation (local or central testing). Patients and/or their legal guardians must sign an informed assent/consent form. Patients will receive either 1.0 mg/kg (6-17 years) or 1.3 mg/kg (3-5 years) of depatux-m every other week intravenously. Primary objectives include evaluating safety, tolerability and pharmacokinetic profile of depatux-m. Since depatux-m displayed frequent, yet reversible, ocular toxicity in adult patients (M12-356 study), ophthalmology examination will be performed throughout the study. The secondary objective will be to determine the tumor response per RANO criteria. Exploratory endpoints include assessing progression-free survival, overall survival, steroid use, and health-related quality of life (HRQOL).
Bim suppresses the development of SLE by limiting myeloid inflammatory responses
Authors: FuNien Tsai, Philip J. Homan, Hemant Agrawal, Alexander V. Misharin, Hiam Abdala-Valencia, G. Kenneth Haines, Salina Dominguez, Christina L. Bloomfield, Rana Saber, Anthony Chang, Chandra Mohan, Jack Hutcheson, Anne Davidson, G.R. Scott Budinger, Philippe Bouillet, Andrea Dorfleutner, Christian Stehlik, Deborah R. Winter, Carla M. Cuda, Harris Perlman
Journal: The Journal of Experimental Medicine (2017)

The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysMCreBimfl/fl) develop a systemic lupus erythematosus (SLE)–like disease that mirrors aged Bim−/− mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, autoantibodies (including anti-DNA IgG), and a type I interferon signature. LysMCreBimfl/fl mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain–containing adapter-inducing interferon-β) is essential for GN, but not systemic autoimmunity in LysMCreBimfl/fl mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.
TMIC-50. DELINEATING THE THERAPEUTIC MECHANISM OF DEXAMETHASONE IN GLIOBLASTOMA-RELATED CEREBRAL EDEMA
Authors: Cameron Herting, Dmitry Shayakhmetov, Dolores Hambardzumyan
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common and aggressive primary brain tumor. During disease progression, nearly all patients will develop cerebral edema. Standard treatment for cerebral edema has been the corticosteroid dexamethasone for over 50 years. Although efficacious in decreasing edema, recent data from our lab and others indicates that dexamethasone administration is associated with reduced median survival when analyzing both stratified data from human patients as well as data generated with murine models. This has been attributed to interference of dexamethasone with standard radiation and chemotherapy. Therefore, it is necessary to develop a therapy for glioblastoma-related cerebral edema that is as effective as dexamethasone, but with decreased side effects. The inflammatory cytokine IL-1 has been referred to as the master regulator of neuroinflammation. It is primarily produced by macrophages; a cell population that can constitute up to 30-50% of the tumor in glioblastoma. This work demonstrates the ability of dexamethasone to inhibit IL-1 expression in primary, bone marrow-derived macrophages following stimulation with lipopolysaccharide and interferon gamma. Moreover, it illustrates the ability of dexamethasone to suppress induction of inflammation-related genes following stimulation with recombinant IL-1. Ongoing investigations utilizing RCAS/tv-a modeling of glioblastoma in IL-1-/- mice will elucidate the role of IL-1 in development of cerebral edema in vivo. Overall, this project demonstrates the role of IL-1 in the therapeutic efficacy of dexamethasone for treating cerebral edema and lays the groundwork for therapies that specifically target IL-1.
P1.01-004 Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC
Authors: D.R. Camidge, M. Ahn, K. Reckamp, H. West, R. Huber, C. Langer, L. Bazhenova, N. Leighl, W. Reichmann, D. Kerstein, D. Kim
Journal: Journal of Thoracic Oncology (2017)
NIMG-31. IMMEDIATE POSTOPERATIVE MRI USE IN PAEDIATRIC BRAIN TUMOUR SURGERY
Authors: William White, Hesham Zaki, John McMullan, Saurabh Sinha, Patricia De Lacy, Shungu Ushewokunze
Journal: Neuro-Oncology (2017)

Intraoperative MRI (IoMRI) is a valuable tool in paediatric neurosurgery to maximize brain tumour resection rates. The availability of this technology worldwide is limited due to high costs. An alternative is to perform a post-op MRI under the same general anaesthetic with a view of returning to theatre if deemed appropriate. We report 8 years experience using immediate post-operative MRI scans for the evaluation of paediatric brain tumour resection. Eighty-three children (median age 7 years; range 0-17 years) underwent 106 operations with an immediate post-op MRI between January 2006 and December 2014. We retrospectively reviewed the time taken to obtain an MRI scan as part of the surgical procedure. The mean total anaesthetic time was 498 minutes (n = 102, SD = 137, range = 194 - 910). Mean transfer time to MRI was 39 minutes (n = 102, SD = 18.5, range = 13 - 94). Mean MRI time was 34 minutes (n = 102, SD = 8.5, range = 12-59). Mean total time from beginning transfer to end of MRI scan was 73 minutes (n = 106, SD = 20.6, range = 41-135). Three patients were taken back to theatre for further tumour resection. The use of immediate post operative MRI scans adds on average just over an hour to total procedure time. This approach is a feasible alternative to IoMRI in paediatric brain tumour surgery in a resource-limited setting.
Solitary Orbital Metastasis in Carcinoma Esophagus
Authors: Sonia Mahajan, Mark P. Dunphy, Sofia Haque, Neeta Pandit-Taskar
Journal: Clinical Nuclear Medicine (2017)

Orbital metastasis is an uncommon and atypical presentation of recurrent esophageal cancer that has been only seldom reported in literature. F-FDG PET/CT is routinely performed for staging and response assessment in patients with esophageal carcinoma. This case demonstrates use of follow-up FDG PET/CT scans in characterizing solitary metastatic disease in orbit and in evaluating response to therapy. It also highlights a key teaching point that postradiation-related inflammatory/infective changes may interfere in accurate assessment of PET/CT scan; however, frequently used clinical and radiological correlation may not be entirely sufficient to rule out pathological involvement.