tbuckley/cabot-search huggingface dataset:
ATIM-27. INTRATUMORAL ADMINISTRATION OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN MALIGNANT GLIOMA PATIENTS: ASSESSMENT OF MUTATIONAL RESPONSE CORRELATES
Authors: David Ashley, Annick Desjardins, Matthias Gromeier, Andrea Muscat, James Herndon, Allan Friedman, Henry Friedman, Frances McSherry, Dina Randazzo, Katherine Peters, Stevie Threatt, Chevelle Bullock, Elizabeth Miller, Susan Boulton, Eric Lipp, Darell Bigner, John Sampson
Journal: Neuro-Oncology (2018)

The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report results of the dose finding trial evaluating PVSRIPO delivered intratumorally by convection-enhanced delivery (CED). Eligible patients were adults with recurrent supratentorial WHO grade IV MG; solitary tumor 1–5.5cm in diameter; 4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS70%; and positive anti-polio titer. A total of 61 pts were treated on study. Only one DLT was observed, a grade 4 intracranial hemorrhage at the time of catheter removal on DL5. Study related adverse events consisted of localized peritumoral inflammation, triggering neurologic symptoms in relation to the location of the infused tumor. Of the 26 patients treated more than 36 months ago, six are alive at 73.6+, 72.5+, 60.6+, 44.0+, 39.3+, and 36.9+ months. Deep sequencing of biopsy material obtained prior to PVSRIPO infusion in 31 samples, confirmed that a very low mutational load is associated with longer survival (p=0.017). Additionally, no patients whose tumors had >0.5 non-synonymous mutations per Mb survived beyond 18 months. CONCLUSION: Infusion of PVSRIPO via CED is safe and encouraging efficacy results were observed in adults along with mutational correlates of response.
Response to: ‘Will SPAR be useful in the usual patients with scleroderma?’ by Chattopadhyay <i>et al</i>
Authors: Wanlong Wu, Suzana Jordan, Oliver Distler
Journal: Annals of the Rheumatic Diseases (2018)

Thank you very much for your interest in our article ‘Prediction of progression of interstitial lung disease in patients with systemic sclerosis: the SPAR model’1 and your precious questions ‘Will SPAR be useful in the usual scleroderma patients?’.2 We are glad to respond as below.

The external validity of the patients recruited is unclear. The authors may like to provide their cohort numbers and how many of them fulfilled the inclusion criteria.

Regarding the question on the external validity of the study cohort, we would like to stress that our study cohort focused on patients with mild interstitial lung disease (ILD) on high resolution computer tompgraph (HRCT), without defining a limit for forced vital capacity (FVC). That is the reason why our patients had an average normal FVC. We disagree that patients with milder ILD and normal FVC are uncommon in clinical practice—please see our recent study.3 In fact, many patients with (milder) ILD might be missed if only lung function testing is used for screening.

However, we agree that these patients have not been included in recent interventional clinical trials such as scleroderma lung study …
Abstract 14442: Ten-year Trends in Coronary Calcification in Individuals Without Clinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis
Authors: Diane E Bild, Robyn McClelland, Joel Kaufman, Roger Blumenthal, Gregory Burke, J. Jeffrey Carr, Wendy Post, Thomas Register, Steven Shea, Moyses Szklo
Journal: Circulation (2012)

Background. Coronary heart disease (CHD) incidence has declined significantly in the US, but whether trends in subclinical atherosclerosis mirror this trend is not known. We determined the secular ...
NIMG-19. SEX-SPECIFIC BRAIN MAPS FOR RISK OF SEIZURE AMONG GLIOMA PATIENTS
Authors: Sara Ranjbar, Barrett Anderies, Kyle Singleton, Sandra Johnston, Cassandra Rickertsen, Akanksha Sharma, Alyx Porter, Maciej Mrugala, Leland Hu, Joseph Mitchell, Joshua Rubin, Kristin Swanson
Journal: Neuro-Oncology (2018)

PURPOSE: Despite a growing body of research on the etiology of seizures in the brain tumor population, it is not yet clear why approximately one third of this population presents with seizure. In this retrospective study we seek to assess the impact of tumor location on the risk of seizure among male and female glioma patients, respectively. From our multi-institutional database, we selected adult patients with contrast-enhancing gliomas (any grade) and known seizure-presentation status at initial diagnosis. Tumors were segmented on pretreatment T2-FLAIR, T2, and post-gadolinium T1 (T1Gd) MR sequences. We warped cortical and subcortical probabilistic atlases to patient images and estimated tumor burden (%) on structures within each lobe and the deep brain. We calculated risk of seizure for various levels of tumor burden and used the result to create sex-specific risk-maps<./p> Our cohort included 128 patients (47 females, 81 males) among whom tumors presented with seizure in 34% of females (n=18) and 58% of males (n=47). Patients with tumors in deep brain structures were identified as at risk for seizure in both males and females. In female patients T2 hyperintensity on 44% of right frontal lobe or 28% of left parietal lobe seem to have an estimated 50%+ risk of seizure. Data indicate that in male patients with left-sided tumors, T2 hyperintensity on 30% or more of frontal, temporal, or parietal lobes results in 50%+ risk of seizure. Male patients with right side tumors, showed a similar level of risk for T2 presence in lateral ventricles and parietal lobe. This study reveals that the risk of seizure is specific to the location of glioma, the percentage of tumor burden, and patient sex. These differences could be considered in patient management decisions to more selectively prescribe anticonvulsants and optimize patient care.
STEM-15. CDK5 AND NOTCH SIGNALING CROSSTALK DRIVES SELF-RENEWAL IN GSCs
Authors: Subhas Mukherjee, Hannah Lee, Leah Broger, Cheryl Olson, Daniel Brat
Journal: Neuro-Oncology (2018)

While the connection between stem cell biology, deregulation of self-renewal properties in glioma stem cells and involved signaling pathways which inherent and/or adaptive to tumor cell resistance has long been considered an important area of cancer research, studies on glioma stem cell self-renewal mechanisms has not always been forthcoming. In this regard, the role of atypical Cyclin Dependent Kinase 5 (CDK5) and its pathway in maintaining self-renewal properties has been characterized. CDK5 is a cyclin dependent kinase family member that does not regulate cell cycle directly. CDK5 is highly important for the survival of post-mitotic neurons and its aberrant activation has been instrumental in neurodegenerative diseases. Our research, as well as that of others, has identified CDK5 as a regulator of self-renewal in glioma stem cells (GSCs). In this capacity, the CDK5 directly activates CREB1 transcription factor independent of PKA/cAMP pathway to drive self-renewal. In the current study we have shown that CDK5 signaling is also a regulator of NOTCH1 activation. Notch pathway regulates self-renewal and asymmetric division through activation of Hes1 transcription factor. Notch pathway is also regulated by Numb and TRIM3 in GSCs and interestingly, TRIM3 regulates CDK5 activity. Our study unravels a signaling crosstalk between CDK5 and NOTCH1 in regulating self-renewal of GSCs.
Abstract 16387: Preventing Cardiovascular Disease and Sudden Cardiac Death by Pre-screening Athletes
Authors: Kaitlyn Greeley
Journal: Circulation (2015)

Background: Cardiovascular disease (CVD) and sudden cardiac death (SCD) among young athletes (YA) remains consistent and continues to influence preventative practices and pre-screening debate. In the United States, screening for SCD in young athletes follows the American Heart Association 12-step screening questions focusing on personal history, family history, and physical examination. The European Society of Cardiology (ESC) outlines a pre-participation screening (PPS) method to minimize SCD and cardiac arrest (CA) by using family history, athlete’s history in sports, physical examination, and a resting 12-lead ECG. Negative findings allow athlete to continue with sports, whereas positive findings require athletes to continue with additional diagnostic tests (echo, stress test, etc.) Method: Using the U.S. National Registry of Sudden Death in Athletes from the National Heart, Lung, and Blood Institute Working Group, we analyzed the annual mortality rates of sudden cardiac death in young athletes in the U.S. compared to the sudden cardiac death rates as reported through the Veneto study. Results: In a 1980-2006 study, using the U.S. National Registry of Sudden Death in Athletes, 1866 sudden deaths were evaluated finding 690 cases were correlated to CVD, with a leading cause of hypertrophic cardiomyopathy. Research shows that every 3 days in the U.S., we lose an athlete to SCD. A study from 1979-2004 in the Veneto region in Italy reported an annual SCD incidence of 1.9 deaths/100,000 person-years in screened young athletes and 0.79 deaths/100,000 person-years in unscreened nonathletic participants. Additionally, the study found an 89% decrease in SCD in athletes with 3.6/100,000 person-years from 1979-1980 and a reported 0.4/100,000 person-years in 2003-2004. Conclusion: In the U.S., 690 sudden cardiac deaths out of 1866 sudden deaths (leading cause as hypertrophic cardiomyopathy) may have been detected using the PPS by adding an ECG to the pre-screening examination. It remains significant that the Veneto study demonstrated little change in SCD in unscreened non-athletes throughout 1979-2004 but notes a significant 89% decrease in SCD in screened athletes paralleling with the 1982 implementation of pre-participation screening.
VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease
Authors: John F. Keaney, Clifford J. Rosen
Journal: New England Journal of Medicine (2018)

The use of dietary supplement products is common in the United States. The National Health and Nutrition Examination Survey, conducted from 1999 through 2012, showed that more than half the adults in the United States consumed dietary supplements.1 In the past decade, the numbers of persons who supplemented their diets with fish oil increased by a factor of 10 and with vitamin D by a factor of 4.1 But any long-term health benefits from these products remain in doubt. Hence, the results from the Vitamin D and Omega-3 Trial (VITAL), a randomized, double-blind, placebo-controlled trial (with a two-by-two factorial design) . . .
Abstract 17: Controlled Progressive Elevation Maximizes Cerebral Perfusion Pressure During Head up CPR in a Swine Model of Cardiac Arrest
Authors: Johanna C Moore, Bayert Salverda, Michael Lick, Carolina Rojas-Salvador, Guillaume Debaty, Nicolas Segal, Keith G Lurie
Journal: Circulation (2018)

Background: Elevation of the head and thorax (HUP) during cardiopulmonary resuscitation (CPR) has been shown to result in a doubling of brain blood flow with higher Cerebral Perfusion Pressures (CerPP) after prolonged active compression-decompression (ACD) CPR with an impedance threshold device (ITD). However, the optimal angle and speed of elevation are unknown. Methods: In study A, in an anesthetized female 40 kg pig model of untreated ventricular fibrillation for 8 min, different HUP angles were assessed (20°, 30°, 40°) in a randomized manner each over a 5-minute periods of ACD+ITD CPR. Based upon study A results, study B was performed, wherein animals were randomized to the two following sequences: 20°, 30°, 40° or 40°, 30°, 20° using the same protocol. The primary endpoint was mean ± SD CerPP (mmHg) for both studies. Results: In study A, 18 pigs were studied. Overall, there was no optimal HUP angle: CerPP was 36 ± 19 for 20°, 42 ± 21 for 30°, and 44 ± 27 for 40° (p = 0.57). However, CerPPs were higher if 40 o HUP was performed during the last 5 minutes of the resuscitation (77 ± 17), versus 20 o HUP and 30 o HUP (44± 18, p = 0.003), suggestive of a sequence effect. To test this hypothesis, study B then enrolled additional animals to compare two elevation sequences 20°, 30°, 40° (n = 6) or 40°, 30°, 20° (n = 5). At 15 min of CPR, the CerPP for 20°, 30°, 40° group was 60 ± 17 and for 40°, 30°, 20° the CerPP was 23 ± 19 (p = 0.01). CerPPs were higher for the 20°, 30°, 40° group throughout the resuscitation (Figure 1). Coronary perfusion pressure was also significantly higher in the 20°, 30°, 40° group (50 ± 17 mmHg versus 22 ± 16 mmHg, p = 0.036) Conclusions: There did not appear to be an optimal HUP angle during ACD+ITD CPR. By contrast, there was an optimal HUP sequence (20,30,40) that resulted in significantly higher CerPP, suggesting controlled progressive elevation is important when performing HUP CPR as compared to an absolute immediate elevation of the head and thorax.
IMMU-04. OVERCOMING IMMUNE EVASION IN GLIOBLASTOMA
Authors: Erin Simonds, Edbert Lu, Lauren McHenry, Pavlina Chuntova, Hideho Okada, William Weiss, Mats Hellstrom
Journal: Neuro-Oncology (2018)

The negative phase 3 trial of anti-PD-1 in human glioblastoma (GBM) contradicts preclinical data showing eradication of GL261 mouse brain tumors by checkpoint inhibitors (CPI). To understand whether the tumor microenvironment contributed to this discrepancy, we immunoprofiled 19 human GBM tumors by CyTOF mass cytometry. We observed a macrophage-rich, T cell-poor microenvironment, with low PD-L1 expression. In contrast, GL261 tumors showed substantial T cell infiltration and high PD-L1 expression. Seeking a model that more accurately reflects the immune landscape of human GBM, we immunoprofiled SB28, a C57BL/6-derived transplantable model of GBM driven by PDGFB, NRASG12D, and p53 loss. CyTOF analysis of SB28 revealed a macrophage-rich, T cell-poor, PD-L1-low microenvironment that recapitulates human GBM. Surprisingly, the efficacy of CPI (anti-PD-1 + anti-CTLA-4) treatment in SB28 was site-dependent. Subcutaneous SB28 flank tumors were eradicated by CPI in all mice, whereas intracranial tumors were refractory. CyTOF analysis revealed that MHC-II+ intratumoral macrophages were twice as frequent in subcutaneous versus intracranial tumors. Similarly, dendritic cells were abundant in subcutaneous tumor-draining lymph nodes, but absent in intracranial tumor-draining (cervical) lymph nodes. Mice previously cured of subcutaneous tumors rejected intracranial tumors upon rechallenge. Taken together, these results suggest that subcutaneous tumors allow superior antigen presentation, resulting in priming and sustained immunological memory after CPI. We then investigated FLT3-ligand, an essential cytokine for dendritic cell maturation, as a therapy to improve antigen presentation in mice with intracranial tumors. We administered recombinant FLT3-ligand intraperitoneally for 10 days after engraftment of intracranial tumors in naive hosts. FLT3-ligand dramatically increased the frequency of dendritic cells and CD8+ T cells in spleens and cervical lymph nodes. Notably, FLT3-ligand monotherapy also caused durable rejection of intracranial tumors in 30% of mice. These results indicate that sufficient T cell priming can confer immunological control of GBM, even in a macrophage-rich, T cell-poor microenvironment.
ACTR-69. BLOOD DERIVED EXOSOMAL hTERT mRNA - A POTENTIAL BIOMARKER FOR GLIOBLASTOMA
Authors: Orit Uziel, Einat Beery, Meir Lahav, Ramez Abu Shkara, Shlomit Yust-Katz, Alexandra l Amiel, Andrew Kanner, Yoseph Laviv, Tali Siegal
Journal: Neuro-Oncology (2018)

Primary glioblastoma multiforme (GBM) have a high proportion (~80%) of TERT-expressing tumors, indicating that this is the primary mechanism of telomerase (hTERT) activation. Exosomes are nano-sized secreted vesicles containing nucleic acids and proteins, which reflect the content of the mother cells. We have previously shown that hTERT transcripts in serum exosomes may serve as a “pan-cancer” diagnostic method, reflecting the load of hTERT in systemic cancer cells. The goal of the current study was to evaluate whether exosomal hTERT may serve as a circulating biomarker for GBM. hTERT mRNA levels were determined in serum derived exosomes obtained from 20 GBM patients and 45 healthy controls. The level of exosomal hTERT mRNA was measured prior to surgery in all GBM patients. In 10 patients additional longitudinal evaluation was performed in blood samples obtained prior to and after concurrent radio/chemotherapy and again during adjuvant temozolomide treatment. Circulating hTERT transcripts were absent in controls and were variably detected in 40% of GBM patients with significantly elevated mean level at diagnosis (p=0.049). These transcripts were gradually downregulated on longitudinal evaluations and during treatment period with significant reduction observed after 3 months of adjuvant treatment when compared to initial sampling (p=0.026). In 10 patients an analysis of hTERT promoter mutation was performed and in 8/10 one of the two common mutations (C228T and C250T) was detected on tumor samples. hTERT mRNA levels may reflect the tumor burden and the clinical status of patients with GBM. In systemic tumors exosomal hTERT mRNA expression is detected in about 60% of cases while in GBM the percentage is probably lower. In patients with detectable levels, this assay may serve as a serum biomarker. These results warrant further confirmation and an update on an extended cohort of patients will be presented at the meeting.
Synergistic effects of benzo[a]pyrene and ultraviolet radiation on primary human keratinocytes
Authors: Rebecca Crallan, Eileen Ingham, Michael N. Routledge
Journal: Cancer Research (2005)

4770  With the recognition that ultraviolet light is a major causative factor in the development of human skin cancer, interest has arisen on understanding the mechanism of action of sunlight in exposed tissues. Ultraviolet light is one of the best-characterized environmental carcinogens, able to function as both a tumor initiator and a tumor promoter. In this regard, it is generally thought that UVB irradiation (ultraviolet radiation in wavelengths from 280 to 320 nm) and to a much lesser extent UVA (ultraviolet light in wavelengths from 320 to 400 nm) is responsible for sunlight-induced cancers. Presumably, the carcinogenic process is initiated by DNA damage. DNA damage in response to UVB light occurs by the direct formation of pyrimidine (6-4) pyrimidone photodimers (6-4 photoproducts) and cyclobutane pyrimidine dimers (thymine dimers), as well as through the formation of reactive oxygen intermediates (ROI) including superoxide anion, hydrogen peroxide and hydroxyl radicals. Our laboratory has been interested in understanding the mechanism by which UVB light generates ROI in sun exposed tissues. We have previously found that endogenous photosensitizers mediate the formation of hydrogen peroxide in keratinocytes. In the present studies we demonstrate that UVB light can generate hydroxyl radicals in aqueous medium in the absence of photosensitizers. Hydroxyl radicals were measured using terephthalate, a water soluble trap whose hydroxylated product is intensely fluorescent. Hydroxyl radical formation was dose-dependent (5-25 mJ/cm2) and required low concentrations of chelated iron (0.3-3 μM). No hydroxyl radicals were observed in the absence of chelated iron indicating that irradiation of aqueous medium initially generates superoxide anion and/or hydrogen peroxide. In further studies using plasmid DNA unwinding assays, we found that ROI formed by UVB light could readily damage DNA. We observed both single and double strand breaks. Hydroxyl radical formation and DNA damage by UVB light were completely blocked by the hydroxyl radical specific scavenger dimethyl sulfoxide (0.1%). Catalase also inhibited hydroxyl radical formation and DNA damage indicating that the reaction was mediated in part by hydrogen peroxide. Taken together, our data demonstrate that low doses of UVB light can readily generate hydroxyl radicals and DNA damage at low concentrations of iron. Moreover, endogenous photosensitizers are not required for UVB light-induced production of ROI. Supported by NIH grants ES05022, ES007148, CA093798 and CA100994.
PATH-21. ANGIOTENSINOGEN GENE SILENCING PREDICTS BEVACIZUMAB RESPONSE IN RECURRENT GLIOBLASTOMA PATIENTS
Authors: Thomas Urup, Linn Gillberg, Signe Michaelsen, Ib Christensen, Helle Broholm, Ulrik Lassen, Kirsten Groenbaek, Hans Poulsen
Journal: Neuro-Oncology (2018)

Bevacizumab in combination with chemotherapy has shown activity in recurrent glioblastoma patients, with responding patients having improved survival as well as quality of life. Recently, we found that low gene expression of angiotensinogen (AGT) was predictive for bevacizumab response in recurrent glioblastoma patients. Because promoter methylation of AGT has been associated with AGT gene silencing, we investigated if AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in recurrent glioblastoma patients. The study includes 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both RANO response and biomarker evaluable. DNA methylation of 7 CpG sites in the CEBPA binding site (~200 bp from TSS) of the AGT promoter was measured using pyrosequencing. AGT gene expression in tumor tissue was measured by NanoString analysis. For each CpG site, methylation levels were associated with angiotensinogen gene expression using Spearman correlations and to treatment response using Mann-Whitney U test and logistic regression analysis. Preliminary results on 58 of 82 patients analyzed: AGT gene expression was inversely associated with AGT promoter methylation on CpG site 1 (P= 0.049) and borderline significant on CpG site 2 (P= 0.074). Compared to non-responding patients, responders expressed significantly higher methylation levels of CpG site 1 (P= 0.015), 2 (P= 0.013) and 3 (P= 0.045). DNA methylation levels at CpG site 4–7 were not associated with AGT gene expression or response. By univariate analysis, increased methylation of the AGT promoter region were predictive for bevacizumab response on CpG site 1 (2-fold increase: OR= 1.81; 95%CI: 1.02–3.23; P= 0.043) and on CpG site 2 (2-fold increase: OR= 2.08; 95%CI: 1.04–4.17; P= 0.040). Increased methylation of the AGT promoter regions is associated with AGT gene silencing and is predictive for bevacizumab response in recurrent glioblastoma patients. Updated results will be presented.