tbuckley/cabot-search huggingface dataset:
NIMG-11. IDENTIFYING EARLY INDICATORS OF IMMUNOTHERAPEUTIC RESPONSE: CAR T-CELL THERAPY
Authors: Gustavo De Leon, Sandra Johnston, Andrea Hawkins-Daarud, Kyle Singleton, Pamela Jackson, Cassandra Rickertsen, Spencer Bayless, Alyx Porter, Maciej Mrugala, Bernard Bendok, Analiz Rodriguez, Behnam Badie, Prativa Sahoo, Russell C Rockne, Christine Brown, Kristin R Swanson
Journal: Neuro-Oncology (2017)

The current guideline to assess radiological changes in response to immunotherapy, iRANO, faces critical challenges in the determination of progressive disease during the first 6 months from the start of therapy. In patients with recurrent glioblastoma (GBM), immunotherapy induces an inflammatory response that mimics progressive disease, which can lead to premature discontinuation of potentially effective therapy. We investigated the dynamics of tumor growth within the first month of starting immunotherapy with the goal of identifying early indicators that could suggest clinical response. We performed a retrospective review of 8 patients from a Phase 1 Trial of CAR T-Cell therapy that had one MRI scan prior to treatment, during treatment and following treatment. Spherically equivalent radii were extracted from tumor volumes segmented on T1Gd and FLAIR MRIs to quantify the dynamics of tumor growth. Kaplan Meier and Cox Proportional Hazard analysis were performed to the role of tumor dynamics in predicting patient survival. Initial tumor growth velocity during CAR T-cell therapy of >50 mm/year (P=0.0067) was prognostic for overall survival from the time of treatment. An increase in radial T1Gd tumor size of >25% (P=0.046) after receiving two CAR T-Cell cycles also discriminated patient survival from the start of treatment. In addition to the above noted optimal cutoffs, initial T1Gd tumor growth velocity was significant as a continuous variable in cox proportional hazard (HR=0.976, P=0.0404). This significance was retained when controlling for age and sex (HR=0.961, P=0.0429). In this case, more aggressive imageable growth was beneficial to the patient. This increased tumor growth rate may be suggestive of a robust immunological response early in therapy that may be important to anticipate in the clinical management of GBM patients. Increased initial tumor growth velocity during treatments shows promise in identifying patients experiencing clinically relevant response that is predictive of patient survival.
MNGI-04. PATHWAY ANALYSIS OF RADIATION-INDUCED MENINGIOMAS REVEALS UPREGULATION OF INFLAMMATORY PATHWAYS IN TUMORS WITH NF2-FUSION
Authors: Suganth Suppiah, Sameer Agnihotri, Mamatjan Yasin, Gelareh Zadeh, Ken Aldape, Jeff Liu
Journal: Neuro-Oncology (2017)

As more pediatric cancer patients are surviving into adulthood from improved oncological therapy there is an increase in the long-term sequelae of treatment. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate significantly different biology than sporadic meningiomas (SMs) and demonstrate clinically more aggressive behaviour. RIMs have been shown to not harbor mutations in common SM associated driver genes, such as NF2, TRAF7, KLF4, PIK3CA and SMO; however, a subset of RIMs have genomic rearrangements with NF2 gene fused to a reciprocal gene, which was previously not seen in SMs. We aimed to compare and contrast the gene expression in RIMs with and without the NF2-fusion event. A primary cohort of 7 RIMs with NF2-fusion and 12 RIMs with wildtype NF2 had RNA sequencing performed using the Illumina HiSeq platform. RNA-Seq expression profiles were analyzed using edgeR, available through BioConductor. Gene Set Enrichment Analysis was performed using Cytoscape®. Principle component analysis of the RNA-Seq data showed that 5/7 RIMs with NF2-fusion were similar to one another. One of the outliers was the only NF2-fusion RIM without a 1p chromosomal arm loss. Significant differentially expressed genes included IGF-1 (log2 of fold change or logFC = 4.14, p=2.65E-05), MME (logFC = 3.03, p = 3.56E-03) and MMP16(logFC = 2.47, p=8.14E-03). Notably, the pathway analysis demonstrated that there was an upregulation of immune/inflammation pathways involving PD-1, STAT-4, IGF-1 and other genes in RIMs with NF2-fusion compared to RIMs with NF2 wildtype. RIMs with the NF2-fusion event have a distinct gene expression profile, with upregulation of inflammatory pathways. Further studies need to be performed to validate these findings using immunohistochemistry. These results suggest that NF2-fusion RIMs may be candidates for immunotherapy.
ACTR-41. INTERIM RESULTS OF FIRST-IN-HUMAN STUDY USING NATIVIS VOYAGER™ SYSTEM IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)
Authors: Garni Barkhoudarian, Charles Cobbs, Edward McClay, Brian Vaillant, J Paul Duic, Burt Nabors, Benjamin Ellingson, Deborah Sheffield, Santosh Kesari
Journal: Neuro-Oncology (2017)

The Nativis Voyager® ulRFE™ system, a non-invasive investigational device, was studied in a first-in-human feasibility study to assess safety and feasibility of the treatment for recurrent glioblastoma (GBM). The anti-mitotic therapy delivers ultra-low radio frequency energy (ulRFE) produced by changes in molecular electrostatic surface potential to the brain. In this prospective, multi-center trial, patients with GBM, following recurrence after receiving standard-of-care chemotherapy and/or radiotherapy were considered for the study. Patients were treated with Voyager alone or with Voyager plus concurrent chemotherapy or Avastin at the discretion of the investigator. Safety was assessed by incidence of any adverse events associated with the investigational therapy. Tumor progression at 8 weeks (2 cycles) was assessed by radiological response by local site. Patients were followed at least every 8 weeks during treatment and every 4 months thereafter. Fourteen patients were enrolled and treated at four clinical sites across the United States. Eleven subjects were followed per protocol in the first stage of a two-stage study. Three subjects withdrew consent prior to the first radiological assessment (day 28) for reasons not associated with the study or investigational therapy, and were not included in the analysis. The local site reported a partial response in the first 2 months of treatment in 2 of the 11 subjects. These subjects were Avastin-naïve. Two were reported to be progression free after 6 cycles (24 weeks) of treatment. No serious adverse events associated with the investigational therapy were reported. Interim results of the second stage of the study will be presented at SNO. The Nativis Voyager appears to be feasible and safe for the treatment of recurrent GBM. Given that therapy is delivered non-invasively, and no serious adverse events attributed to the investigational therapy were reported, further prospective study of the investigational device is warranted.
OA 12.05 Spectrum of 1,014 Somatic BRAF Alterations Detected in Cell-Free DNA of Patients with Advanced Non-Small Cell Lung Cancer
Authors: V. Raymond, T. Bivona, R. Lanman, R. Nagy, K. Banks, Y.K. Chae, J. Clarke, J. Crawford, D.R. Gandara, J. Heymach
Journal: Journal of Thoracic Oncology (2017)
Abstract 21153: The Atrial Fibrillation Ethnic Paradox: Insights From National Inpatient Sample Database
Authors: N. Gurukripa Kowlgi, Sampath Gunda, Santosh Padala, Kenneth A Ellenbogen
Journal: Circulation (2017)

Introduction: It has been reported that African-American (AA) patients have lower incidence of atrial fibrillation (AF) as compared to their Caucasian (C) counterparts. However, precise differences in incidence of the traditional risk factors in the above groups have not been described in large population cohorts. Hypothesis: To confirm and further delineate previously reported ethnic trends in AF patients amongst AA and C. Methods: We retrospectively analyzed 8,080,123 hospitalized patients between the years 2011-2013 from the National Inpatient Sample database. All patients with a principal diagnosis of AF based on ICD-9-CM code of 427.31 (n = 932,303, 11.5%) formed the study cohort and were further sub-categorized into C and AA cohorts. Chi-square and one-sample T test were used to compare the traditional risk factors between AA and C patients with AF. Results: AF incidence in C was 12.9% vs 5.5% in AA (p &lt; 0.001). AA were younger (69.57 ± 28.49 years vs. 76.81 ± 23.2 years, p &lt; 0.05 ) and had less men (46.6% vs. 49.9%). AAs had higher prevalence of hypertension (75.9% vs. 70%), congestive heart failure (26.5% vs. 23.3%), diabetes mellitus with (8.4% vs 5.3%) or without complications (33% vs. 25.2%), renal failure (35.5% vs. 22.2%), obesity (16.6% vs. 11.8%), smoking (8.4% vs 6%) and alcohol consumption (3.9% vs. 2.7%). C however had a higher prevalence of coronary atherosclerosis (41.7% vs 35.9%). All of the above were statistically significant with a p-value &lt; 0.001 with 95% confidence intervals. Conclusion: Our data demonstrates a significant AF ethnicity paradox. Despite higher prevalence of traditional risk factors for AF, AA had &gt;2-fold lower incidence of AF compared to Cs. Possible hypothesis for the above includes under-diagnosis of AF in AA, age differences, or yet unknown pathophysiological features of AF. While the former can be addressed with vigilant clinical practice, the latter would need further research.
Abstract 11781: α1-syntrophin Mutation Identified in Drug-induced Long-QT Syndrome Increases Late Sodium Current
Authors: Jong-Il Choi, Chaojian Wang, Geoffrey S Pitt
Journal: Circulation (2015)

Introduction: Drug-induced long-QT syndrome (diLQTS) is an acquired disorder, often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Recent data suggest that the late sodium current (INa-L) augments the proarrhythmic effect of IKr inhibition, but few mutations in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. Hypothesis: We hypothesized whether a novel SNTA1 mutation (p.E409Q) found in a patient with diLQTS increases INa-L, thereby providing a mechanism for diLQTs in this patient. Methods: Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild-type (WT) or SNTA1 mutants (A390V-previously reported mutation in congenital LQTS; and E409Q), and in adult rat ventricular cardiomyocytes, which were infected with adenoviruses expressing either the WT or one of the two SNTA1 mutants. Results: In HEK293T cells, there was no significant difference in the peak INa densities at -30 mV among the WT and the mutants. However, INa-L (% of peak current) was increased in both mutants (0.58±0.10 in WT vs. 0.90±0.11 in A390V, p=0.048; vs. 0.88±0.07 in E409Q, p=0.023). In adult rat cardiomyocytes, peak INa densities at -40 mV were similar among the WT and the mutants. INa-L was significantly increased in E409Q-SNTA1, not in A390V-SNTA1 compared to WT-SNTA1 (0.49±0.14 in WT vs.0.94±0.23 in A390V, p=0.099; vs. 1.12±0.24 in E409Q, p=0.019). Conclusions: We demonstrated that a novel SNTA1 mutation is likely causative for diLQTS by augmenting INa-L. These data suggest the mutation of the NaV1.5-interacting α1-syntrophin is a potential mechanism for the genetic susceptibility in patients with diLQTS, thereby expanding the concept that mutations within congenital LQTS loci can cause diLQTS.
TMIC-06. IMMUNE MICROENVIRONMENT IN CYSTIC GBM
Authors: Zhihua Chen, Yong-Ming Qiu
Journal: Neuro-Oncology (2017)

The study objective was to characterize the immune microenvironment in cystic glioblastoma (GBM). We retrospectively reviewed the records of 298 consecutive newly diagnosed and recurrent adult GBM patients treated at our hospital from Jan 2011 to Jun 2017. 23 (7.7%) had cystic tumors and 17 had cystic tumor components. We were able to analyze 23 of these cystic GBM (cGBM) cases. We observed that overall survival in cGBM group is longer than in noncystic counterparts. In 17 samples, 16 were PTEN+, and all of these had TILS CD3, CD4, CD8 within the tumor and in surrounding vessels, 7/17 cGBM were PDL-1+ (>1%). T cells (CD8+, CD4+, and CD8+CD4+), B cells and NK cells were detected in the cystic fluid of cGBM cases. T memory cells (CD4+CD25-CD127+) but not Treg cells were also detected in the cystic fluid. The proportion of active T cells (CD69+) in the cystic fluid was higher than in control PBMC. Immunosuppressive cells Treg and MDSC populations were lower in the cystic fluid than in PBMC. The ProcartaPlex Human Cytokine Panel (34 plex) and IPA data analysis a variety of chemokines were detected in the GBM cyst fluid. IL-6, GRO-alpha, IL-8, IP-10, MCP-1, TNF-a, IL-4, IL-27 were higher in the peripheral blood serum cGBM patients versus non-cystic GBM patients; however, the inhibitory cytokine IL-10 is lower in cyst fluid or PB serum. These results suggest that the mechanism of cystic formation in cGBM could be due to activation of the host immune system. Higher levels of chemokines in the cystic fluid of cGBM patients could enhance recruitment of lymphocytes into the tumor. Intact PTEN status as observed in 16/17 cGBM patients in our study, is critical for anti-glioma immune function and may have played a role in improved survival in our study.
P2.03-005 Overall Survival Results from a Prospective, Multicenter Phase II Trial of Low-Dose Erlotinib as Maintenance in NSCLC Harboring EGFR Mutation
Authors: S. Hirano, G. Naka, Y. Takeda, M. Iikura, T. Hiroishi, K. Shikano, A. Yanagisawa, N. Hayama, T. Fujita, H. Amano, M. Nakamura, S. Nakamura, H. Tabeta, H. Sugiyama
Journal: Journal of Thoracic Oncology (2017)
Overlapping Surgery—Opportunities in Neurosurgery Based on New Research
Authors: David B. Hoyt
Journal: JAMA Surgery (2017)

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MA 17.08 The Validity of TNM Classification After Induction Treatment in Patients with NSCLC: Pulmonary Resection with or Without Induction Treatment
Authors: H. Melek, G. Cetinkaya, E. Özer, E. Yentürk, T. Sevinç, T. Evrensel, A. Bayram, C. Gebitekin
Journal: Journal of Thoracic Oncology (2017)
CSIG-25. REGULATION OF GLIOBLASTOMA BIOENERGETICS BY AMP KINASE
Authors: Biplab Dasgupta, Rishi Raj Chhipa
Journal: Neuro-Oncology (2017)

As tumors evolve, they undergo metabolic state transitions in response to flux of nutrients, O2, and therapy. The evolving cancer-genome undergoes several intended and unintended mutations, amplifications, insertions and deletions. These dynamic changes create metabolic vulnerability and impose great burden on cancer cells. To thrive, evolving cancer cells acquire a remarkably altered metabolic and signaling flexibility. Identifying genes that protect tumor cells against cell-intrinsic vulnerabilities and the hostile tumor environment may provide novel therapy in human cancer. The multifunctional kinase AMPK is an evolutionarily conserved energy/stress sensor that plays important yet undefined role during tumor evolution. AMPK activated by the tumor suppressor LKB1 or the calcium-regulated kinase CAMKK2. AMPK inhibits mTOR and lipogenesis and therefore not surprisingly, many laboratories found that agents (e.g., metformin, now in several clinical trials) that activate AMPK suppress tumor growth. However, a few recent studies questioned this over-simplistic model. Using glioblastoma multiforme (GBM) as a model, we found that the AMPK pathway is constitutively active in human GBM and in a clinically relevant genetically engineered mouse model of high grade glioma. The AMPK-HIF1 alpha axis was earlier shown to play a tumor suppressive role in a mouse model of lymphoma. Unexpectedly, we uncovered that the AMPK-HIF1 alpha axis plays a tumor promoting role in GBM. Biochemical, genetic and metabolic experiments showed that AMPK positively regulates a HIF1alpha and GABPA-dependent transcriptional program of GBM bioenergetics that allows optimal energy metabolism and survival. Unfortunately, there are no specific AMPK inhibitors. Therefore, using multiple genetic tools to reduce, or express (rescue) targets of the AMPK- HIF1alpha-GABPA pathway in vivo and in vitro, we observed that AMPK is essential for GBM growth and survival.
SURG-03. SUBCORTICAL STIMULATION MAPPING OF DESCENDING MOTOR PATHWAYS FOR PERIROLANDIC GLIOMAS: ASSESSMENT OF MORBIDITY AND FUNCTIONAL OUTCOME IN OVER 700 PATIENTS
Authors: Seunggu Jude Han, Irene Troncon, Ramin Morshed, Kesshi Jordan, Roland Henry, Mitchel S Berger
Journal: Neuro-Oncology (2017)

We report our experience with intraoperative stimulation mapping to locate the descending subcortical motor pathways in patients undergoing surgery for hemispheric gliomas within or adjacent to the rolandic cortex, and describe the morbidity and functional outcomes associated with this technique. The retrospective analysis included 702 patients undergoing resection of hemispheric perirolandic gliomas within or adjacent to descending motor pathways. Data regarding intraoperative stimulation mapping results and patient postoperative neurological status were collected. Of 702 patients, stimulation mapping identified the descending motor pathways in 300 cases (45%). New or worsened motor deficit was seen postoperatively in 210 cases (30%). Of these 210 cases, there was improvement in the motor function to baseline by 3 months postoperatively in 160 cases (76%), while the deficit remained in 50 cases (24%). Majority (56%) of long-term deficits were mild or moderate (antigravity or better). Patients in whom the subcortical motor pathways were identified during surgery with stimulation mapping were more likely to develop an additional motor deficit postoperatively compared to those in whom the subcortical pathway could not be found (45% vs. 19% respectively, p<0.001). This difference also remained when considering the likelihood of a long-term deficit (i.e. persisting >3 months; 12% vs. 3.2%, p<0.001). A significant region of diffusion restriction around the resection cavity was seen in 20 patients with long-term deficits and was more common in cases when the motor pathways were not identified. Thus, long term deficits that occur in settings where the subcortical motor pathways are not identified seem in large part due to local ischemic injury to descending tracts. Stimulation mapping allows surgeons to identify the descending motor pathways during resection of tumors in perirolandic regions and to achieve an acceptable rate of morbidity in these high risk cases.
Hepatitis C in sub-Saharan Africa: the current status and recommendations for achieving elimination by 2030
Authors: Mark W Sonderup, Mary Afihene, Reidwaan Ally, Betty Apica, Yaw Awuku, Lina Cunha, Geoffrey Dusheiko, Neliswa Gogela, Marie-Jeanne Lohouès-Kouacou, Phillip Lam, Olufunmilayo Lesi, Papa Saliou Mbaye, Emmanuel Musabeyezu, Betty Musau, Olesegun Ojo, John Rwegasha, Barbara Scholz, Abate B Shewaye, Christian Tzeuton, Chris Kassianides, C Wendy Spearman
Journal: The Lancet. Gastroenterology & hepatology (2017)
Brain radiotherapy (RT) and immunotherapy (IT) for metastatic melanoma (MM): a retrospective single institution experience
Authors: G. Galli, S. Cavalieri, L. Di Guardo, C. Cimminiello, F. Corti, F. Nichetti, M. Garcia, S. Tana, C. Fallai, F. de Braud, M. Platania, M. Del Vecchio
Journal: Annals of Oncology (2017)
P2.03-027 Comparative Longitudinal Toxicity Analysis of EGFR Mutated NSCLC Treated with Either Pemetrexed Carboplatin or Gefitinib
Authors: M. Sharma, V. Patil, A. Joshi, V. Noronha, A. Bhattarjee, S. Goud, S. More, A. Ramaswamy, A. Karpe, N. Pande, A. Chandrasekharan, A. Goel, V. Talreja, K. Prabhash
Journal: Journal of Thoracic Oncology (2017)
P2.01-065 Clinico-Radiological and Pathological Evaluation of Lung Adenocarcinoma with Infiltration on the Computed Tomography of the Chest
Authors: A. Okada, S. Choh, T. Nakai, C. Ohbayashi, Y. Kurono, M. Ueda, K. Katayama, N. Koguchi, S. Murakami, H. Takenaka
Journal: Journal of Thoracic Oncology (2017)
Abstract 17612: Hypertension Severity is Associated With Impaired Cognitive Performance
Authors: Henrique C Muela, Valeria A Costa-Hong, Michel F Machado, Natália C Moraes, Claudia M Memória, Mônica S Yassuda, Edson B Shu, Ricardo C Nogueira, Ayrton R Massaro, Raul R Feitosa, Silvia Merlin, Eduardo S Trés, Ricardo Nitrini, Alfredo J Mansur, Luiz A Bortolotto
Journal: Circulation (2015)

B: Hypertension affects the target-organs diversely. Most evidence on target-organ damage in hypertension is related to kidney and heart. The cerebrovascular and cognitive impairment are less studied. O: To study the cognitive function changes in patients with hypertension on different stages compared to the control pairs and their correlation with the arterial stiffness properties assessed by non-invasive methods and cerebral circulation assessed by transcranial Doppler. M: In a cross sectional study 162 patients (42 controls and 120 hypertensive) were comparatively evaluated. Hypertensive patients were divided in three stages according to the blood pressure levels or medication use (HTN-1: BP 140-159/90-99 or use of one antihypertensive drug; HTN-2: BP 160-179/100-109 or use of two drugs and HTN-3: BP ≥180/110 or use of three or more drugs). The following variables were evaluated: pulse wave velocity, intima medial thickness, cerebral blood flow velocities by transcranial Doppler (TD) and cognitive function. Mean velocity of middle cerebral artery was continuously monitored at resting and during the breath holding test (30 seconds) and 3 minutes handgrip maneuver. Cognitive function was assessed by mini mental state examination and Montreal Cognitive Assessment. R: Compared to control group, HTN-3 group was older, had higher BMI, IMT and PWV and lower educational level and family income (Table 1). Interestingly, the higher the hypertension stage the poorer was the performance in cognitive tests even after age correction. There was no difference among the groups related to TD velocities at rest and the hand-grip maneuver. However, it was noted a lower breath holding index in the hypertensive group (HTN-1=0.94±0.56; HTN-3=0.97±0.59 vs Control=1.5±0.68; p=0.002) which could infer less vasomotor reactivity in these patients. C: Cognitive impairment was more frequent in patients with hypertension and this frequency was related to hypertension severity.