tbuckley/cabot-search huggingface dataset:
CBMT-32. IMAGING A HALLMARK OF CANCER: TERT EXPRESSION LEADS TO MRS-DETECTABLE METABOLIC REPROGRAMMING
Authors: Pavithra Viswanath, Russell Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2018)

Hotspot promoter mutations reactivate expression of telomerase reverse transcriptase (TERT) in mutant IDH1 oligodendrogliomas. TERT expression allows glioma cells to avoid telomere dysfunction-induced senescence, thereby enabling limitless proliferation. Since TERT expression is essential for glioma proliferation and TERT inhibitors are attractive therapeutic targets, identification of metabolic biomarkers of TERT expression will facilitate non-invasive imaging of tumor status and response to therapy. Therefore, the goal of this study was to identify 1H- and hyperpolarized 13C-magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression in mutant IDH1 glioma cells. We studied mutant IDH1-expressing immortalized normal human astrocytes without (NHApre) and with TERT expression (NHApost and NHAtert). Using 1H-MRS we monitored steady-state metabolite levels and analyzed the data in an unbiased manner using principal component analysis. Our results indicated that the metabolic profile of NHApre cells differed significantly from that of NHApost and NHAtert. Elevated levels of glutathione (GSH, reduced), NADPH, NADH, aspartate and taurine in NHApost and NHAtert cells relative to NHApre were responsible for this discrimination. These results identify 1H-MRS-detectable biomarkers of TERT expression in mutant IDH1 glioma cells. Next, we used 13C-MRS to examine [2-13C]-glucose flux to the pentose phosphate pathway (PPP) since the PPP is a major source of NADPH, which, in turn, maintains GSH levels. PPP fractional flux was significantly higher in NHApost and NHAtert cells relative to NHApre, consistent with higher levels of NADPH and GSH in the TERT-expressing models. Importantly, the flux of hyperpolarized [U-13C]-glucose to the PPP intermediate 6-phosphogluconate was elevated in NHApost and NHAtert cells relative to NHApre, thereby identifying hyperpolarized [U-13C]-glucose as a potential imaging biomarker of TERT status. Collectively, our study links TERT expression to significant metabolic reprogramming in mutant IDH1 gliomas and identifies 1H- and hyperpolarized 13C-MRS biomarkers that may be valuable for monitoring tumor TERT status and response to therapy.
Innovative imaging methods in heart failure: a shifting paradigm in cardiac assessment. Position statement on behalf of the Heart Failure Association of the European Society of Cardiology
Authors: Jelena Čelutkienė, Carla M. Plymen, Frank A. Flachskampf, Rudolf A. de Boer, Julia Grapsa, Robert Manka, Lisa Anderson, Madalina Garbi, Vassilis Barberis, Pasquale Perrone Filardi, Paola Gargiulo, Jose Luis Zamorano, Mitja Lainscak, Petar Seferovic, Frank Ruschitzka, Giuseppe M.C. Rosano, Petros Nihoyannopoulos
Journal: European Journal of Heart Failure (2018)
Abstract 280: Cardiac Deletion of the Mitochondrial Pyruvate Carrier Results in Dilated Cardiomyopathy with Preservation of Fatty Acid Catabolism
Authors: Kyle S McCommis, Carrie M Gierasch, Attila Kovacs, Carla J Weinheimer, Timothy R Koves, Deborah M Muoio, Brian N Finck
Journal: Circulation Research (2017)

Pyruvate is an important metabolic substrate for the heart that is formed in the cytosol by glycolysis or conversion of lactate, and then must be transported into the mitochondrial matrix for further metabolism. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 proteins that are each required for complex stability and transport activity. Indeed, mice with cardiac-specific knockout of MPC2 (CS-MPC2-/- mice) exhibited concomitant MPC1 degradation and marked reduction in pyruvate-stimulated mitochondrial respiration. While cardiac function and heart size was normal in 6 week old CS-MPC2-/- mice, serial echocardiograms demonstrated drastic increases in heart size, chamber dilation, and loss of contractile function at 10 and 16 weeks of age. Gene markers of heart failure, hypoxia, and fibrosis were markedly increased in CS-MPC2-/- hearts. Mitochondria isolated from 16 week old failing CS-MPC2-/- hearts exhibited normal respiration on glutamate/malate, succinate, palmitoylcarnitine, and 3-hydroxybutyrate/malate, indicating preservation of mitochondrial energetics with anaplerotic malate, or substrates to produce acetyl-CoA independent of pyruvate. Expression of genes encoding fat and ketone oxidation enzymes was not down-regulated in failing CS-MPC2-/- hearts as is typically observed in heart failure, suggesting these hearts may rely on fat or ketone body oxidation for ATP production. However, targeted metabolomics of hearts from 6 week old CS-MPC2-/- chow-fed mice suggested TCA cycle dysfunction due to decreased acetyl-CoA levels that are insufficient to condense with oxaloacetate, causing an accumulation of oxaloacetate/aspartate, malate, and fumarate. To determine whether increasing the availability of usable substrates (fatty acids and ketones) would rescue the cardiac dysfunction, CS-MPC2-/- mice were fed a high fat, low carbohydrate (ketogenic) diet. Ketogenic diet strikingly decreased hypertrophy and improved functional parameters in 10 week old mice. In conclusion, loss of mitochondrial pyruvate utilization leads to altered cardiac substrate metabolism and inability to maintain TCA cycle flux, resulting in dilated cardiomyopathy that can be corrected by administration of a ketogenic diet.
TMIC-19. USING QUANTITATIVE MR IMAGING TO RELATE GBM MASS EFFECT TO PERFUSION AND DIFFUSION CHARACTERISTICS OF THE TUMOR MICRO-ENVIRONMENT
Authors: Daniel Abler, Prativa Sahoo, Kathryn Kingsmore, Jennifer Munson, Philippe Büchler, Russell Rockne
Journal: Neuro-Oncology (2018)

Biomechanical forces are known to affect tumor growth and evolution [1]. Likewise, tumor growth drives physical changes in the micro-environment that affect tissue solid and fluid mechanics. Tumor mass effect, resulting from rapid tumor cell proliferation, has been shown to be prognostic for poor outcome in glioblastoma (GBM) patients and to be associated with the expression of gene signatures consistent with proliferative growth phenotype [2]. Similarly, elevated interstitial fluid flow (IFF) has been shown to drive GBM invasion [3]. This study investigates the relationship between tumor mass effect, diffusion, perfusion and IFF in GBM using anatomical (pre- and post-contrast T1 weighted, T2/FLAIR) and quantitative MR imaging (Dynamic Contrast Enhanced (DCE) MRI, and Diffusion Weighted Imaging (DWI)). We use data from 39 patients from the Ivy Glioblastoma Atlas Project (Ivy GAP)[4] which provides matched imaging, ISH, RNA, gene expression and clinical data over the course of treatment. We analyze pre-operative anatomic imaging data to determine the tumor-induced mass effect in each patient using quantitative measures such as ‘Lateral ventricle displacement’ [2]. Perfusion and diffusion measures are derived from pre-operative DCE and DWI imaging. Additionally, we estimate IFF velocities in the tumor region using DCE imaging data in combination with a computational model of fluid flow [5]. We will report the results of quantitative imaging analysis in relation to tumor mass effect and examine correlations with biological tumor characteristics and treatment outcome. We further investigate our findings in patient-derived xenograft models of GBM. References: [1] R.K. Jain et al. Annu. Rev. Biomed. Eng., 2014, 16, 321–346. [2] T.C. Steed et al. Scientific Reports, 2018, 8, 2827. [3] K.M. Kingsmore et al. Integr. Biol., 2016, 8 1246-1260 [4] N. Shah et al. Data from Ivy GAP. The Cancer Imaging Archive 2016. [5] K.M. Kingsmore et al. APL Bioengineering (In press).
NCMP-23. FACIAL PALSY INDUCED BY CANCER IMMUNOTHERAPY: A SINGLE CENTER RETROSPECTIVE STUDY
Authors: Carlen Yuen, Pankti Reid, Betty Soliven, Zuoli Zhang, Jason Luke, Kourosh Rezania
Journal: Neuro-Oncology (2018)

Monoclonal antibodies to Cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) [ipilimumab] and programmed cell death (PD1) receptor or ligand (PDL1) [pembrolizumab, nivolumab, atezolizumab] are increasingly used for the treatment of metastatic cancer. The augmented immune response enabled by these agents leads to the emergence of a class of side effects called immune-related adverse effects (irAEs) manifesting as autoimmune-like diseases. Neuromuscular complications such as polyneuritis, Guillain Barré syndrome (GBS)and myasthenia gravis are the most common; facial paralysis is only rarely reported. In this retrospective study, we reviewed the records of 364 patients who underwent immunotherapy in our center, for facial paralysis and Bells palsy, and identified five patients: 4 males and 1 female, ages 39 to 68 (average 55 years old) at the time of occurrence of facial paresis. Four patients had metastatic melanoma, all were treated with ipilimumab, in combination with nivolumab or pembrolizumab in 3 and 1 patients, respectively; the remaining patient had metastatic bladder and was treated with atezolizumab. Facial paralysis occurred within 1–23 weeks after starting immunotherapy and was unilateral in four patients. One patient had a multifocal neuropathy affecting limb and multiple cranial (including right facial) nerves; unilateral facial paresis emerged during the course of a GBS like condition in another patient. Lymphocytic pleocytosis was seen in CSF of three patients who had a lumbar puncture, MRI showed enhancement of the intracranial portion of the affected facial nerve in 4 patients. All but one patient, who had concomitant herpes labialis, were treated with steroids, with complete or significant improvement in 4; in the 5th patient facial weakness was still present after 3 months, before being lost to follow up. Facial paralysis is a less frequent neurological irAE, 1.4% in our cohort, and usually has a good prognosis.
Characteristics of Patients With Professional Guardians in the Department of Veterans Affairs Health Care System
Authors: Andrew B. Cohen, Mark Trentalange, Andrea Z. Benjamin, Terri R. Fried
Journal: JAMA Internal Medicine (2018)

Among the most vulnerable patients encountered by health care professionals are those with impaired capacity who are represented by a professional guardian, defined as a paid official who is a stranger and is selected by a judge to act as a surrogate.Recent articles in the national media have documented abuse by professional guardians, 1 and case reports have suggested that professional guardians often fail to make highquality medical decisions. 2Even rudimentary information about patients with professional guardians is not known, however, because data about guardianship are not kept. 3How many patients have professional guardians, who these patients are, why they are impaired, and why the court becomes involved in selecting surrogates for them remain unclear.We sought to identify and characterize a population-based sample of patients with professional guardians using records from the Department of Veterans Affairs (VA), because courts in many jurisdictions are required to notify the VA when a guardian is appointed for a veteran.
Holistic services for people with advanced disease and chronic breathlessness: a systematic review and meta-analysis
Authors: Lisa Jane Brighton, Sophie Miller, Morag Farquhar, Sara Booth, Deokhee Yi, Wei Gao, Sabrina Bajwah, William D-C Man, Irene J Higginson, Matthew Maddocks
Journal: Thorax (2018)

Background Breathlessness is a common, distressing symptom in people with advanced disease and a marker of deterioration. Holistic services that draw on integrated palliative care have been developed for this group. This systematic review aimed to examine the outcomes, experiences and therapeutic components of these services. Methods Systematic review searching nine databases to June 2017 for experimental, qualitative and observational studies. Eligibility and quality were independently assessed by two authors. Data on service models, health and cost outcomes were synthesised, using meta-analyses as indicated. Data on recipient experiences were synthesised thematically and integrated at the level of interpretation and reporting. Results From 3239 records identified, 37 articles were included representing 18 different services. Most services enrolled people with thoracic cancer, involved palliative care staff and comprised 4–6 contacts over 4–6 weeks. Commonly used interventions included breathing techniques, psychological support and relaxation techniques. Meta-analyses demonstrated reductions in Numeric Rating Scale distress due to breathlessness (n=324; mean difference (MD) −2.30, 95% CI −4.43 to −0.16, p=0.03) and Hospital Anxiety and Depression Scale (HADS) depression scores (n=408, MD −1.67, 95% CI −2.52 to −0.81, p&lt;0.001) favouring the intervention. Statistically non-significant effects were observed for Chronic Respiratory Questionnaire (CRQ) mastery (n=259, MD 0.23, 95% CI −0.10 to 0.55, p=0.17) and HADS anxiety scores (n=552, MD −1.59, 95% CI −3.22 to 0.05, p=0.06). Patients and carers valued tailored education, self-management interventions and expert staff providing person-centred, dignified care. However, there was no observable effect on health status or quality of life, and mixed evidence around physical function. Conclusion Holistic services for chronic breathlessness can reduce distress in patients with advanced disease and may improve psychological outcomes of anxiety and depression. Therapeutic components of these services should be shared and integrated into clinical practice. Registration number CRD42017057508.
CSIG-09. THE ROLE OF HYDROGEN SULPHIDE IN GLIOMAS
Authors: Farhana Akter, Parisa Nikrouz
Journal: Neuro-Oncology (2018)

Glioblastoma is the most common malignant brain tumour in adults, with high relapse rates and a dismal prognosis. Despite advances in our understanding of the pathobiology of the condition, a curative treatment has yet to be found. Hydrogen sulphide (H2S) is a multifunctional novel gasotransmitter, which has recently garnered interest in the tumour biology field. However, little is known about this molecule in glioblastoma. A systematic review of the literature was thus undertaken to determine whether H2S and its synthesizing enzymes play a significant role in the glioma tumour biology. A total of 108 published articles were identified in our systematic search of electronic databases (PUBMED, WEB OF SCIENCE). After screening for eligibility, a total of seven studies investigating the role of sulphur, H2S and H2S synthesizing enzymes underwent comprehensive review, quality assessment, and data extraction. H2S synthesising enzymes CBS, CSE and MPST were increased in glioma cells compared to normal non-tumour cells in all the studies. The MPST enzyme appears to be particularly abundant in glioma cells. The CBS enzyme was shown to have a beneficial role in glioma, and when deficient led to increased angiogenesis and tumour growth. H2S produced from cysteine is stored as bound sulphane sulphur. Levels of sulphane sulphur was shown to be raised in high grade gliomas compared to normal human brain regions and were thought to be involved in tumour proliferation. The underlying mechanisms of H2S -induced effects in glioma cells were investigated in only three studies. Although there is a clear evidence of the presence of H2S or its synthesising enzymes, the role of H2S in glioma has not been fully delineated. A thorough understanding of the molecular mechanisms underlying its action in glioma and in vivo studies investigating its affect on tumour growth and survival are warranted.
Abstract P368: Carotid Intima-Medial Thickness is Associated with Silent Brain Infarctions: The Atherosclerosis Risk in Communities Study
Authors: Melissa C Caughey, Ye Qiao, Rebecca F Gottesman, Thomas H Mosley, Beverly Gwen Windham, Bruce A Wasserman
Journal: Circulation (2017)

Background: Carotid intima-medial thickness (IMT) is an indicator of subclinical atherosclerosis and medial hypertrophy, and is easily quantified by ultrasonography. Although carotid IMT has been associated with systemic cardiovascular disease, its relation to silent brain infarctions (SBI) is not well established. The etiology of SBI is multifactorial; likely causes include atherosclerotic and thrombotic obstructions, microthrombi, and lipohyalinosis. Because arterial IMT reflects both atherogenesis and hypertensive remodeling, we hypothesized that elevated carotid IMT would be associated with SBI. Methods: The Atherosclerosis Risk in Communities (ARIC) study is an observational cohort of 15,792 black and white participants from 4 US communities. At visit 3 (1993-1995) a subset of stroke-free study participants (N=1,346) was screened by brain MRI and carotid ultrasound. IMT was averaged bilaterally, from 12 posterior wall measurements along a 1 cm segment of the distal common carotid artery up to the bifurcation. Consistent with European Society of Cardiology recommendations, IMT &gt; 0.9 mm was considered elevated. Asymptomatic brain lesions ≥3 mm in diameter were considered SBI. Prevalence ratios (PRs) for number of SBI lesions associated with elevated IMT were analyzed using Poisson regression, adjusted for age, race-center, sex, current smoking, hypertension, diabetes, and hyperlipidemia. Model fit was ascertained by the deviance to degree of freedom ratio. Results: Of 1,346 individuals, 170 (13%) were classified with elevated IMT. Mean IMT was 1.0 ± 0.2 mm vs. 0.7 ± 0.1 mm for those with and without elevated IMT. Study participants with elevated IMT were more often male (49% vs. 38%; p=0.006), black (60% vs. 46%; p=0.0007), and older (64 vs. 62 years; p=0.0001); with a greater prevalence of both hypertension (65% vs. 42%; p&lt;0.0001) and diabetes (27% vs. 13%; p&lt;0.0001). SBI were detected in 157 individuals with a collective total of 247 lesions. A total of 30 (18%) participants with elevated IMT had at least one SBI lesion, compared to 127 (11%) with normal IMT (p=0.009). Elevated IMT was associated with 70% greater number of SBI lesions (PR=1.7; 95% CI: 1.3 - 2.3; p=0.0008). After adjustment for cardiovascular risk factors, elevated IMT remained associated with a 40% greater SBI count (PR= 1.4; 95% CI: 1.0 - 1.9; p=0.05). Conclusions: Although elevated IMT is often classified by a conservative 0.9 mm cut-point, it is a continuum, with advanced wall thickening (&gt;1.5 mm) recognized as plaque. In this analysis from the ARIC Study, asymptomatic individuals classified with elevated IMT had mild wall thickening (mean IMT = 1.0 mm), which nonetheless was associated with greater number of SBI lesions. This association remains robust after adjustment for cardiovascular risk factors.
ACTR-13. A BAYESIAN ADAPTIVE RANDOMIZED PHASE II TRIAL OF BEVACIZUMAB VERSUS BEVACIZUMAB PLUS VORINOSTAT IN ADULTS WITH RECURRENT GLIOBLASTOMA FINAL RESULTS
Authors: Vinay Puduvalli, Jing Wu, Ying Yuan, Terri Armstrong, Jimin Wu, Pierre Giglio, Jihong Xu, Howard Colman, Tobias Walbert, Jeffrey Raizer, Morris Groves, Fabio Iwamoto, David Tran, Nicholas Avgeropoulos, Nina Paleologos, Karen Fink, David Peereboom, Marc Chamberlain, Ryan Merrell, Marta Penas-Prado, W K Alfred Yung, Mark Gilbert
Journal: Neuro-Oncology (2018)

Bevacizumab improves outcome and reduces symptoms in patients with recurrent glioblastoma (GBM). However, GBMs develop adaptive resistance to bevacizumab- mediated angiogenesis inhibition resulting in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor, with pleotropic antiangiogenic effects, would delay emergence of resistance to bevacizumab therapy and improve clinical outcome. In this multicenter phase II trial utilizing a novel Bayesian design, patients with recurrent glioblastoma were adaptively randomized to bevacizumab alone or bevacizumab+vorinostat based on a primary endpoint of progression-free survival (PFS) such that patients had a higher likelihood of receiving the more efficacious treatment. Secondary end points were overall survival (OS) and quality of life assessment (MDASI-BT). Eligible patients were adults (≥ 18 yrs) with histologically confirmed GBMs recurrent after prior radiation and temozolomide therapy, adequate organ function, KPS≥ 60, and no prior bevacizumab/HDAC inhibitors. Ninety patients (bevacizumab+vorinostat:49, bevacizumab:41) were enrolled and 74 were evaluable for PFS (bevacizumab+vorinostat:44, bevacizumab:30). Grade 3 or greater toxicities in 85 evaluable patients included hypertension (n=37), neurological changes (n=2), anorexia (n=2), infections (n=9), wound dehiscence (n=2), DVT/PE (n=2), and colonic perforation (n=1). There was one treatment-related death due to pulmonary embolism. Upon multivariate analysis for bevacizumab+vorinostat vs bevacizumab, median PFS (3.7 vs. 3.9 months, p=0.94, HR 0.63 [95% CI 0.38, 1.06, p=0.08]) or median OS (7.8 vs. 9.3 months, p=0.64, HR 0.93 [95% CI 0.5, 1.6, p=0.79]) were not significantly different between the two arms. Ongoing analyses of patient reported outcomes (MDASI-BT) and plasma biomarkers will be reported. Combining bevacizumab with vorinostat did not result in improved PFS or OS compared with bevacizumab alone in patients with recurrent GBM. This trial is the first to test a Bayesian PFS-based adaptive randomized design in patients with primary brain tumors and demonstrates the feasibility of using adaptive randomization in a multicenter setting.
SURG-17. COMBINED AWAKE CRANIOTOMY AND TRANSCORTICAL MEP FOR RESECTION OF MOTOR AREA GLIOMAS
Authors: Taiichi Saito, Yoshihiro Muragaki, Takashi Maruyama, Manabu Tamura, Masayuki Nitta, Takakazu Kawamata
Journal: Neuro-Oncology (2018)

Resection of primary motor area gliomas have risk of severe motor deficits and it is considered difficult to massive removal. We have actively resected gliomas in this area with combined awake craniotomy and transcortical motor evoked potentials (MEP) since 2005. We presented the removal method and surgical results for tumor in this area, and examined factors related to postoperative motor deficits. The present study included 30 consecutive patients (nine men and nine women; mean age 40 years) with a primary motor area glioma from 2005 to 2017. All tumors were removed with confirming spontaneous movement during awake craniotomy and monitoring transcortical MEP. Postoperative motor deficits were evaluated in four categories: Stable, Declined (Mild, Moderate, Severe). We defined Moderate and Severe as deficits that interfere with daily life. In 28 of 30 cases, an effective waveform was not obtained with transcortical MEP. The mean extent of resection was 93%. Motor deficits at 6 months after surgery were Stable 20, Mild 7, Moderate 2 cases, and Severe one case. Moderate and Severe deficits were confirmed in 3/30 cases (10%). Motor deficits at 6 months after surgery was significantly correlated with declined intraoperative spontaneous movement, decreased transcortical MEP more than 50%, and presence of ischemic lesion postoperative MRI. The patients without declined spontaneous movement with/without decreased transcortical MEP showed no decline of motor function 6 months after surgery (6 patients). While, those with declined spontaneous movement without decreased transcortical MEP showed 20% (2 of 10 patients) of declined cases, and those with declined spontaneous movement with decreased transcortical MEP more than 50%, 67% (8 of 12 patients) of declined cases. CONCLUSIONS: Monitoring of spontaneous movement during awake craniotomy and neurophysiological monitoring by transcortical MEP have complementary relationship, are useful for removal of primary motor area gliomas, and contribute aggressive removal.