tbuckley/cabot-search huggingface dataset:
RBIO-07. TUMOR TREATING FIELDS (TTFIELDS) DELAY DNA DAMAGE REPAIR FOLLOWING RADIATION TREATMENT OF GLIOMA CELLS: IMPLICATIONS FOR IRRADIATION THROUGH TTFIELDS TRANSDUCER ARRAYS
Authors: Moshe Giladi, Mijal Munster, Rosa Schneiderman, Tali Voloshin, Yaara Porat, Ze’ev Bomzon, Eilon D Kirson, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2017)

The EF-14 clinical trial has demonstrated the effectiveness and safety of Tumor Treating Fields (TTFields) application using transducer arrays in patients with ndGBM, starting almost 4 months from diagnosis, during maintenance treatment with TMZ. In the past 3 years, several publications demonstrated that besides exerting anti-mitotic effects, TTFields can also inhibit DNA Damage Repair (DDR), thus leading to enhanced efficacy. Taken together with the fact that in most cancer types an earlier treatment start is favorable, applying TTFields in concomitant with radiotherapy (RT) shortly after diagnosis, has the potential to improve treatment outcome. The goal of the present work was to explore efficacy and safety aspects of TTFields application together with RT. The efficacy of TTFields application after RT was tested in glioma cells based on their survival rates. Effect on DDR was tested using the alkaline comet assay or by analyzing γH2AX or Rad51 foci formation and resolution. RT energy absorption by the transducer arrays was measured by applying RT doses of 2 Gy through the transducers placed on a solid-state phantom. Skin toxicities were tested in rats irradiated with 2 Gy, 5 times a week for 2 weeks through arrays placed on the dorsal skin. Applying TTFields shortly after irradiation, synergistically enhanced the effect of RT in glioma cells. Application of TTFields to irradiated cells impaired DDR, possibly by blocking homologous recombination. The presence of the transducer caused a minor reduction (<4%) in irradiation intensity at 20 mm and 60 mm below the arrays but led to a significant increase (344%) in irradiation dosage at the phantom surface. Transducer arrays on the rat skin during irradiation exposure did not lead to adverse skin reactions. Results support the application of TTFields therapy before and immediately after RT as a viable treatment regimen to enhance the outcome of RT.
PDCT-07. TUMOR TREATING FIELDS FOR PEDIATRIC PATIENTS WITH HIGH GRADE GLIOMA: FIRST CASE SERIES IN GERMANY
Authors: Matthias Wölfl, Elisabeth Miller, Matthias Eyrich, Jürgen Krauss, Paul G Schlegel
Journal: Neuro-Oncology (2017)

Novel treatment options for pediatric patients with high grade glioma are urgently needed to improve the otherwise dismal prognosis. For adult patients suffering from glioblastoma multiforme (GBM) a new treatment modality using alternating electrical fields called tumor treating fields (TTFields), showed efficacy in a randomized clinical trial (Stupp R et. al 2015). These alternating electrical fields are applied via transducer arrays on the shaved scalp to disturb mitosis in dividing cells. Data on the use of TTFields in children so far are limited to singular case publications. We here present our experience with the first three pediatric glioma patients treated with TTFields in Germany. Three patients age 7, 9 and 11 years were treated for anaplastic astrocytoma WHO III (pt.1) and GBM (pt. 2 + 3). Tumors in pt. 1 and pt. 2 could only be partially resected prior to therapy with irradiation and concomitant temozolamide. Pt. 3 underwent complete resection and irradiation, but had to stop temozolamide treatment due to severe thrombocytopenia. This patient underwent a second surgery due to early relapse. All patients started treatment in March 2017 after informed consent and assent on a compassionate use basis. Assent by the children was an important issue and required extra time and additional explanations. Treatment was initiated within 44 days (mean) after the end of irradiation. Pt. 1 and 2 received temozolamide concomitantly, whereas pt. 3 received additional vaccination with tumor-lysate-pulsed dendritic cells. TTFields were implemented well into everyday life, as reported in structured interviews and quality of life assessment. There were no severe side effects observed so far. Average daily usage was high, namely 71%, 86% and 92% respectively. TTFields may be a treatment option for high grade glioma even in young children. The data encourage evaluation of TTFields in children within clinical trials.
Cambios de inmunidad antidiftérica específica por edad en Polonia durante los cuarenta últimos años
Authors: A Zakrzewska, A Galazka, D Rymkiewicz
Journal: Eurosurveillance (1997)

La epidemia masiva de difteria en Rusia y Ukrania que se ha extendido a todos los Nuevos Estados Independientes (NEI) de la ex-URSS (1-5) ha hecho temer por una posible propagacion de la enfermedad a otros paises. Este temor esta justificado porque, en muchos paises industrializados, una gran parte de la poblacion adulta esta mal inmunizada contra la difteria.
ACTR-24. THE ESTIMATED LONG-TERM SURVIVAL BENEFIT OF ADDING TTFIELDS TO THE STANDARD OF CARE FOR GLIOBLASTOMA PATIENTS
Authors: Gregory Guzauskas, Marc Salzberg, Bruce Wang
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most aggressive form of primary brain cancer. The EF-14 trial for GBM patients reported a 5-year survival rate of 12.8%, the first report from a large randomized controlled trial of 5-year survival greater than 10%. The increased survival compared to previous studies was achieved by adding tumor treating fields (TTFields) to the existing standard of care of radiochemotherapy. An understanding of the predicted long-term prognosis for GBM patients is important to facilitate good clinical, personal and policy decision-making, as survival at 5 years continues to improve. To estimate the mean lifetime survival benefit for GBM patients of adding TTFields to the existing standard of care. Standard regression-based parametric extrapolations of overall survival were constructed and were fit to the EF-14 trial data. These models underestimated the reported long-term GBM survival rates. Parametric models assume a constant hazard function, which was not observed in the EF-14 trial or epidemiological data, resulting in the underestimation. Survival was instead modelled using a previously described method that synthesized EF-14 trial data with GBM epidemiological data and general population survival rates. The estimated mean lifetime survival from initiation of adjuvant treatment was 4.2 years with TTFields and 2.4 years without it, an increase of 1.8 years. The estimated incremental life years gained (LYG) was 1.3 years when a 3% discount rate was applied to future survival benefits. TTFields-treated survivors who survived to 2 years were estimated to have a 20.7% chance of surviving to 10 years. The analysis indicated that treating GBM patients with TTFields substantially increased mean lifetime survival, consistent with the clinical findings of the EF-14 trial. Current GBM treatment strategies offer improved prognoses compared to past therapies, and should be considered by physicians, patients and payers in GBM treatment decisions.
P2.16-010 Removing the Chest Tube on the First Day after Surgery Does Not Contribute to the Early Discharge from the Hospital
Authors: T. Ohashi, T. Yoshimasu, M. Kawago, Y. Hirai, M. Miyasaka, Y. Yata, Y. Aoishi, S. Oura, Y. Nishimura
Journal: Journal of Thoracic Oncology (2017)
PATH-36. REPEATING TESTING IN IDH WILD TYPE LGG CASES. THE IMPORTANCE OF NEXT GENERATION SEQUENCING
Authors: Enrico Franceschi, Dario De Biase, Antonella Mura, Alexandro Paccapelo, Alicia Tosoni, Stefania Bartolini, Giovanni Tallini, Annalisa Pession, Daniela Danieli, Sabrina Rossi, Daniela Bartolini, Marina Paola Gardiman, Lorenzo Volpin, Antonio Fioravanti, Vania Ramponi, Elena Zunarelli, Carlo Bortolotti, Michela Visani, Santino Minichillo, Alessio Cubeddu, Enrico Maria Silini, Stefano Pizzolitto, Alba Brandes
Journal: Neuro-Oncology (2017)

The 2016 WHO classification of CNS tumors included molecular parameters in addition to histology to redefine many tumor entities. Low-grade gliomas (LGG) are divided into isocitrate dehydrogenase (IDH) wild type or mutant. Absence of IDH mutation is a rare event in LGG, and IDH wild type is considered a provisional entity by the WHO classification. The technique used to assess IDH mutation is essential to determine the prognosis in this tumor type. the observation of a particularly favorable outcome in a group of 42 patients with IDH wild type LGG (OS=93.7 months) led us to assess IDH mutation with a more sensitive technique. Next Generation Sequencing (NGS) was used to evaluate IDH status in these tumor samples, and the results of NGS assay were compared with previous findings. Initial assessment of IDH mutation in 42 patients had been performed using PCR (90%) or immunohistochemistry (10%). Twenty-one (50%) of the 42 initial IDH wild type LGGs were found to present IDH mutation when tested with NGS. Four patients had R132H mutation and 17 cases showed other IDH mutations (4 patients with IDH2 mutation, 5 patients with IDH1 R132C mutation, 5 patients with IDH1 R132G mutation and 3 patients with IDH1 R132S mutation). Median OS of NGS confirmed IDH mutated LGG was 164.0 months vs 32.2 months for NGS IDH wild type LGG reflecting the distinct clinical course of these two entities. Repeating testing in IDH wild type LGG cases is crucial, as well as the technique used to assess this mutation. NGS is able to find IDH mutations in 50% of patients previously misdiagnosed. IDH wild type LGG remains a rare entity with dismal prognosis.
Abstract 21380: RBM39 is Vital for Maternal Obesity-Induced Fetal Sheep Cardiac Contractile Dysfunction by Regulating Myocardial Autophagy
Authors: Qiurong Wang, John F Odhiambo, Peter W Nathanielsz, Stephen P Ford, Jun Ren, Wei Guo
Journal: Circulation (2017)

Maternal obesity becomes pandemics in 21 st century. Previous epidemiological studies on humans suggested that obesity during pregnancy could result in increased incidences of cardiovascular diseases in the offspring. Studies on animal models also indicated that maternal obesity could induce cardio dysfunction in offspring. However, the mechanisms underlying are still not well elucidated. Previously we have reported that maternal obesity could lead to fetal cardiac contractile dysfunction in sheep. Moreover, from mid- to late-gestation, the cortisol level has been shown increased in fetuses born from obese ewes. Here, we are trying to tie the relationship of upregulated cortisol level in fetuses to maternal obesity-induced fetal cardiac contractile dysfunction. We found that RBM39, a critical transcriptional factor which is activated by hormonal stimulation, was 2.5-fold upregulated in fetal myocardium from obese ewes. Moreover, maternal obesity induced autophagic gene upregulation in fetal myocardium. Meanwhile, the expression of the autophagic cargo protein SQSTM1, also known as ubiquitin-binding protein p62, is also upregulated in maternal obesity fetal hearts. The upregulated SQSTM1 is an indicator of blockade of autophagic flux. Collectively, our studies reveal RBM39 as a transcriptional factor, is activated by increased levels of cortisol in fetuses from mid- to late-gestation. In turn, autophagy pathways have been activated via RBM39 transcriptional regulation in fetal myocardium of fetuses born from obese ewes, as well as the autophagy cargo protein SQSTM1. Therefore, the autophagic flux has been disturbed in the myocardium of fetuses born from obese ewes, which could be a possible mechanism of maternal obesity-induced cardiac contractile dysfunction.
PS01.02 Imaging Guideline-Recommendations Prior to Treatment for Non-Small Cell Lung Cancer Demonstrates Variable Compliance
Authors: J.R. Rayburn, C.L. Wilshire, C.R. Gilbert, B.E. Louie, R.W. Aye, A.S. Farivar, E. Vallières, J.A. Gorden
Journal: Journal of Thoracic Oncology (2017)
ATIM-19. POPULATION PHARMACOKINETIC (PPK) ANALYSIS OF NIVOLUMAB FLAT AND WEIGHT-BASED DOSING REGIMENS AND ASSOCIATIONS WITH SAFETY IN PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM) TREATED IN CHECKMATE 143
Authors: Jun Shen, Matthew Hruska, Ricardo Zwirtes, Von Potter, Prashni Paliwal, Amit Roy, Akintunde Bello, Satyendra Suryawanshi, Michael Lim
Journal: Neuro-Oncology (2017)

Nivolumab 3 mg/kg Q2W was well tolerated in rGBM in CheckMate 143 (NCT02017717). It is unknown if nivolumab PK will differ in rGBM vs other tumor types; therefore, a PPK analysis was performed to compare nivolumab PK in patients with rGBM vs those with NSCLC. Additionally, this analysis was used to determine if exposure or safety will differ with flat (240 mg Q2W) vs weight-based dosing (both approved in multiple tumor types) in rGBM. Nivolumab PK was characterized using samples from patients with rGBM (n=161; CheckMate 143) and NSCLC (n=654; 5 studies). A PPK model incorporating baseline covariates was developed. Post-hoc individual parameters were used to predict exposure with flat vs weight-based dosing. Safety was assessed per CTCAE v4.0. Nivolumab PK was well described by a 2-compartment model with time-varying clearance. Baseline clearance was 45% lower in rGBM (0.149 L/d) than in NSCLC (0.271 L/d); magnitude of clearance decrease over time was also lower (8% vs 30%). Nivolumab exposures (steady-state trough serum concentration) were 45% higher in rGBM than in NSCLC (97.2 vs 66.9 ug/mL); similar exposures (100 ug/mL) were predicted with flat dosing in rGBM. Across exposure quartiles (<103.5 [n=37]; ≥103.5–<117.1 [n=39]; ≥117.1–<131.2 [n=37]; ≥131.2 ug/mL [n=38]) in rGBM (weight-based dosing), AE incidence (any grade) varied from 94.6% to 97.3%, with the incidence of grade ≥3 AEs being 48.6%, 33.3%, 51.4%, and 52.6%, respectively. Nivolumab exposures were higher in rGBM than in NSCLC, which has exposures similar to melanoma and RCC, but were within the range evaluated and considered safe in a dose-escalation study (NCT00730639). Increased nivolumab exposure in rGBM was not associated with an increase in grade ≥3 AEs. Similar exposures were predicted with nivolumab 240-mg and 3-mg/kg Q2W regimens, suggesting that flat dosing is a viable regimen for future GBM studies.
ANGI-12. IDENTIFICATION OF A NOVEL TYROSINE KINASE/INTEGRIN COMPLEX THAT DRIVES BRAIN METASTASES
Authors: Arman Jahangiri, Maxim Sidorov, Alan Nguyen, Garima Yagnik, Sung Won Han, Smita Mascharak, Michael De Lay, Jeffrey Wagner, Brandyn Castro, Brandon Imber, Kan Lu, Gabriele Bergers, William Weiss, Manish K Aghi
Journal: Neuro-Oncology (2017)

Brain metastases, the most common brain tumors, confer a poor prognosis. Studies have suggested roles for β1-integrin and c-Met, but the mechanisms remain unelucidated. We hypothesized that a c-Met/b1integrin complex drives breast cancer cells to metastasize to the brain and elsewhere. We utilized immunoprecipitation, proximity ligation assays (PLAs), and inducible heterodimerization assays. MDA-MB-231 breast cancer cells were injected in mammary fat pads of athymic mice, of which 20% developed metastases. Primary metastasized tumors had 10-fold more c-Met/b1 complexes than non-metastasized tumors (P=0.004). Gastrointestinal and brain metastases demonstrated 12-fold (P=0.0006) and 18-fold (P=0.01) more c-Met/b1 complexes than primary tumors. Inducing c-Met/b1 complex formation through an engineered inducible heterodimerization system reduced cellular circularity shape factor (P=6X10-7), increased scratch assay motility (P=0.001–0.02), increased matrigel invasion (P=0.007), and promoted two of four metastatic cascade steps in vivo: primary site tumor cell migration and extravasation out of circulation. MDA-MB-231-BR brain-seeking cells selected for brain metastatic capacity in vivo exhibited upregulated c-Met/b1 complex levels compared to MDA-MB-231 cells. Biotinylation revealed that complex formation began intracellularly before membrane trafficking. Complex formation promoted ligand-independent allosteric receptor activation, with integrin-linked kinase phosphorylating c-Met and crystallography revealing c-Met/b1 complex to maintain the high-affinity b1 integrin conformation. Far western blotting and sequential immunoprecipitation revealed that c-Met displaced a5 integrin from extracellular binding of b1 integrin, creating a complex with much greater affinity for fibronectin than a5b1. PLA revealed increased c-Met/b1 integrin complexes in patient breast cancer brain metastases compared to paired primary breast tumors from the same patients (P=0.0006–0.004). Metastatic tumor cells co-opt receptors promoting both modes of cell migration: chemotaxis, movement towards chemoattractants, and haptotaxis, movement controlled by peripheral adhesions. Tumor cells redirect these receptors away from their conventional binding partners, forming a powerful c-Met/b1 complex whose ligand-independent cross-activation and robust affinity for fibronectin drives metastases.
SURG-28. KYPHO-IORT: A NEW TREATMENT PARADIGM FOR PATHOLOGICAL FRACTURES
Authors: Shashank Gandhi, Ahmad Latefi, Ferney Diaz Molina, Yu Chen, Maged Ghaly
Journal: Neuro-Oncology (2017)

This is a prospective single institution study to assess the safety and efficacy of Kypho-intraoperative radiation therapy (Kypho-IORT) for potentially mechanically unstable metastatic disease to the spine in reducing pain. Patients with symptomatic osteolytic vertebral body metastasis underwent Kypho-IORT: kyphoplasty procedures and intraoperative radiotherapy with the ZEISS INTRABEAM System followed by cement augmentation. Tumors were limited to vertebral body using the International Spine Radiosurgery Consortium (ISRC) anatomic classification system, SINS scores of 7-12 (potentially unstable), and Bilsky grade 0. Intraoperative CT delineation of gross tumor volume, needle applicator tip, and OAR delineation were done with deformable image registration, integrating pre-operative CT and MRI images. 10 Gy was prescribed to a distance from the source tip to the distal boundary. The prescription was limited by a maximum dose limit to the spinal cord of 12 Gy. Preoperative and postoperative pain scores were assessed with the numerical rating pain scale (NRPS). The involved spine will be imaged at 3-month intervals up to one year. 7 vertebral levels were treated. All patients were discharged home within 12 hours of the Kypho-IORT procedure. There was a statistically significant reduction in patient reported NPRS scores from preoperative baseline within 2 weeks (6.57 ± 2.82 preoperative versus 4.00 ± 2.16 postoperatively; p=0.0349). After 3 months, one patient with metastatic rectal cancer suffered local progression. No patients experience neurological deterioration postoperatively. Kypho-IORT is a safe treatment option for potentially unstable spinal metastases. Patient reported pain scores significantly improve within two weeks, enhancing the patient’s quality of life. Long-term follow up is necessary to further evaluate efficacy.
P2.01-054 Inclusion of Central Nervous System Metastasis in Lung Cancer Early Phase Clinical Trials
Authors: N. Duma, M. Gonzalez Velez, V. Mariotti, R. Carr, E. Schenk, K. Leventakos, J. Molina, A. Mansfield, A. Adjei
Journal: Journal of Thoracic Oncology (2017)
MA 02.11 A Phase I Trial of Erlotinib and Onalespib in EGFR-mutant NSCLC: Focus on EGFR Exon 20 Insertions
Authors: J. Riess, K. Reckamp, J. Longmate, K. Kelly, D.R. Gandara, P. Mack, E. Newman, P. Lara
Journal: Journal of Thoracic Oncology (2017)
TMIC-16. THE IMMUNO-PROTECTIVE FUNCTION OF GLIOMA-ASSOCIATED BONE MARROW DERIVED CELLS DEPENDS ON THE STAGE OF TUMOR GROWTH AND IS INFLUENCED BY TREATMENT WITH MINOCYCLINE
Authors: Sheila Mansouri, Kelly Burrell, Mamatjan Yasin, Sameer Agnihotri, Romina Nejad, Tansy Zhao, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) remains the most aggressive primary brain tumor due to its recurrent nature and inherent ability to evade the current treatment strategies. Non-malignant monocyte lineage cells including monocyte, macrophage, microglia, and dendritic cells, infiltrate the glioblastoma tumor mass and contribute to its growth and homeostasis. These cells can become activated towards an immuno-suppressive and pro-angiogenic state that promotes continued tumor growth. While it was once thought that glioma-associated macrophages and microglia play an anti-tumor role, more recent studies have suggested that tumors may co-opt these immune cells for their own tumor-promoting function. In this study, we assessed the tumor-suppressor and pro-tumor roles of glioma associated macrophages and microglia using the antibiotic minocycline. Minocycline is a non-cytotoxic antibiotic that could be re-purposed, as a single agent or in combination with other medications, to inhibit or reverse immuno-suppression, angiogenesis, and other tumor growth-enhancing roles of microglia and macrophages. We demonstrate that bone marrow-derived cells (BMDCs) that track to mouse gliomas and mature into glioma-associated microglia/macrophages function in either an anti- or pro-tumorigenic manner upon treatment with minocycline, depending on the stage of tumor growth at which this drug is administered. Survival analysis of glioma mouse models indicated that treatment with minocycline immediately after intracrainial injections reduced survival, while delayed treatment increased the survival of mice. In addition, our data indicate that minocycline affects the immune function of BMDCs by altering their ability to phagocytoze tumor cells. This observation was in agreement with changes observed in the expression of genes known to play a role in phagocytosis. These findings strengthen the hypothesis that tumor-resident BMDCs can play a dual anti-tumorigenic or pro-tumorigenic role depending on the stage of tumor growth. As such, targeting these cells with pharmaceutical agents for treatment of gliomas requires detailed understanding of their exact role in the tumors.
P1.07-031 Autoantibodies Associated with Risk of Subclinical Autoimmunity and Immune-Related Adverse Events from Checkpoint Inhibitor Therapy
Authors: D. Gerber, S. Khan, Q. Li, L. Feng, F. Fattah, S. Khan, J. Saltarski, Y. Mccuthchen, X. Luo, Y. Xie, W. Wakeland
Journal: Journal of Thoracic Oncology (2017)
Electronic consultations offer few benefits for GP practices, says study
Authors: Jacqui Wise
Journal: BMJ (2017)

Electronic consultations appear to offer some benefit to patients but increase the workload of GPs, research published in the British Journal of General Practice shows.1

Policy makers have suggested that online consultations could ease pressure on GP practices and improve patient access, but there is limited research on whether they are able to deliver such improvements. Only around 6% of practices have used some form of electronic consultation but a further 20% have plans to do so in the future. There are currently two main e-consultation systems being used in primary care in the …