tbuckley/cabot-search huggingface dataset:
P3.14-013 Outcomes According to Marginal Tumor Dose Prescription for Small- to Medium-Sized Brain Metastases from Lung Cancer
Authors: F. Moraes, J. Winter, H. Raziee, C. Coolens, G. Zadeh, P. Kongkham, M. Bernstein, T. Conrad, N. Laperriere, B. Millar, A. Berlin, D. Shultz
Journal: Journal of Thoracic Oncology (2017)
Empowerment Failure: How Shortcomings in Physician Communication Unwittingly Undermine Patient Autonomy
Authors: Peter A. Ubel, Karen A. Scherr, Angela Fagerlin
Journal: The American Journal of Bioethics (2017)

Many health care decisions depend not only upon medical facts, but also on value judgments-patient goals and preferences. Until recent decades, patients relied on doctors to tell them what to do. Then ethicists and others convinced clinicians to adopt a paradigm shift in medical practice, to recognize patient autonomy, by orienting decision making toward the unique goals of individual patients. Unfortunately, current medical practice often falls short of empowering patients. In this article, we reflect on whether the current state of medical decision making effectively promotes patients' health care goals. We base our reflections, in part, on research in which we observed physicians making earnest efforts to partner with patients in making treatment decisions, but still struggling to empower patients-failing to communicate clearly to patients about decision-relevant information, overwhelming patients with irrelevant information, overlooking when patients' emotions made it hard to engage in choices, and making recommendations before discussing patients' goals.
SCDT-50. SURFACE MODIFIED LIPOSOMES FOR EFFECTIVE DELIVERY OF THERAPEUTIC AGENTS ACROSS THE BLOOD BRAIN BARRIER
Authors: AB Madhankumar, Becky Webb, Oliver Mrowczynski, Xiaoli Liu, Vagisha Ravi, James R Connor
Journal: Neuro-Oncology (2017)

Liposomes are lipid bilayer nanovesicles that have inherent ability to deliver therapeutic and imaging agents to the tumor cells due to enhanced permeability and retention effect (EPR effect) and also by active targeting mechanism. The major hurdles in delivering the therapeutic agents to CNS malignancies are the blood-brain and blood-tumor barriers. Although several drugs are known to cross the blood brain barrier (BBB), they are not effective in eliminating the tumors completely. So a formulation that could enhance their ability to get across the BBB and actively targeting the tumor is necessary to overcome blood brain and blood tumor barrier. We have formulated variety of liposomes by varying the surface molecules and therapeutically active lipids. To determine the feasibility of the liposome formulation to cross the blood brain barrier we developed an in vitro blood brain barrier model using bovine brain microvascular endothelial cells (BBMVEC) cultured as monolayer. Various liposomal doxorubicin formulations were prepared after modifying their surface by protein conjugation, a small molecule inhibitor (farnesyl thiosalicylic acid), a small molecule iron chelator (Dp44mt) and glutathione. All the small molecules were chosen for this study rationally by in silico determination of the feasibility of the molecules to cross the BBB. Moreover, the liposomal doxorubicin was also rationally designed to mimimize the cardiotoxicity mediated by doxorubicin and to synergistically improve the therapeutic efficacy. In vitro cytotoxicity assays were performed in the glioma cell lines. BBB transport studies were performed after culturing bovine brain endothelial cells as monolayer in a transwell system. A time dependent increase in the transport of the compound occurs as evidenced by the in vitro BBB model. In vivo investigation reveals the transport of the targeted liposomes through the blood brain barrier after intravenous administration of the liposomes, as evidenced by fluorescent microscopic images of the mouse brain tissue.
MNGI-03. VOXEL-BASED LESION MAPPING TECHNIQUE REVEALS THE SPATIAL DISTRIBUTION OF MENINGIOMAS
Authors: Hirayama Ryuichi, Manabu Kinoshita, Hideyuki Arita, Daisuke Eino, Naoki Kagawa, Yasunori Fujimoto, Haruhiko Kishima
Journal: Neuro-Oncology (2017)

Recent studies have reported strong associations between tumor locations, clinical features and genetic alterations in meningiomas. Although several predilection sites including cerebral convex, parasagittal areas or several skull base regions have been well-documented, those evaluations were traditionally based on descriptive methods. This study aimed to re-evaluate preferential areas of meningiomas more accurately by means of voxel-based lesion mapping (VBLM) and three-dimensional (3D) image rendering techniques. Magnetic resonance images of a consecutive series of 248 cases with treatment naïve 260 meningiomas were retrospectively analyzed. All images were registered to a T1-weighted brain atlas provided by the Montreal Neurological Institute (MNI152), and a lesion frequency map was created followed by 3D volume rendering to visualize the predilection sites of the tumors. In order to evaluate the validity of the cohort, the frequencies of tumor locations were compared with the results of previous publication including the Japan Brain Tumor Registry (JBTR). The 3D lesion frequency map clearly showed the preferential areas of meningiomas including the cerebral convexity and skull base regions. In parasagittal areas, the mid one-third of the superior sagittal sinus was most commonly affected. Substantial lesion accumulation was observed around the leptomeninges covering the central sulcus and the Sylvian fissure while very few lesions were observed at the frontal, parietal and occipital convexities. In skull base areas, parasellar, sphenoid wing and petroclival regions were commonly affected by the tumor. In the descriptive evaluation, frequencies for the tumor incidences in each area including the cerebral convex or falx, parasellar region were comparable with previous reports. The VBLM technique successfully visualized the meningioma predilection areas on the 3D lesion frequency map, and particularly indicated the preference of the mid-third area among the parasagittal regions. These observations warrant further studies for meningioma biology using this technique.
P3.01-075 Afatinib Dose Adjustment: Effect on Safety, Efficacy and Patient-Reported Outcomes in the LUX-Lung 3/6 Trials in EGFRm+ NSCLC
Authors: V. Hirsh, E. Tan, Y. Wu, L. Sequist, C. Zhou, M. Schuler, S. Geater, T. Mok, C. Hu, N. Yamamoto, J. Feng, K. O’Byrne, S. Lu, Y. Huang, M. Sebastian, I. Okamoto, N. Dickgreber, R. Shah, M. Palmer, A. Märten, D. Massey, C. Samuelsen, J.C. Yang
Journal: Journal of Thoracic Oncology (2017)
PDCT-09. TEMOZOLOMIDE WITH IRINOTECAN VERSUS TEMOZOLOMIDE, IRINOTECAN PLUS BEVACIZUMAB FOR RECURRENT MEDULLOBLASTOMA/CNS PNET OF CHILDHOOD: REPORT OF A COG RANDOMIZED PHASE II SCREENING TRIAL
Authors: Adam Levy, Mark Krailo, Susan Chi, Chris Williams-Hughes, Mary Bancroft, Doojduen Villaluna, Maryam Fouladi, Amar Gajjar
Journal: Neuro-Oncology (2017)

Despite aggressive therapy including surgery and chemotherapy with or without radiation, approximately 30 percent of children with medulloblastoma (MB) experience recurrence which is usually incurable. The purpose of this study was to compare the overall survival (OS) of patients receiving the combination of temozolomide (TMZ) and irinotecan with that of patients receiving TMZ, irinotecan and bevacizumab for recurrent MB/CNS Primitive Neuroectodermal Tumor (PNET). Patients with relapsed/refractory MB or CNS PNET were randomly assigned to receive TMZ (150 mg/m2/day PO on days1-5) and irinotecan (50 mg/m2/day IV on days 1-5) with or without bevacizumab (10 mg/kg IV on days 1 and 15). Enrollment required evidence of tumor by CNS imaging. 107 patients were treated on study. Overall, 24 patients completed 12 courses of planned protocol therapy, 27% in the experimental arm with bevacizumab vs. 18% in the standard arm. EFS and OS each improved by 3 months in the bevacizumab arm. Median EFS was 6 months in the standard arm and 9 months with the addition of bevacizumab, and median OS was 16 months in the standard arm and 19 months with the addition of bevacizumab. For OS, the hazard ratio from the stratified relative risk regression model is 0.71. Toxicity profiles were comparable in both treatment arms. The estimate of the incidence of feasibility events associated with the bevacizumab arm is 3/52=5.7% (95% CI 1.2%-16%). Events included myelosuppression, electrolyte abnormalities, diarrhea and elevated transaminases. One intracranial hemorrhage event was observed in each arm. The addition of bevacizumab to TMZ/irinotecan improved OS in children with recurrent disease. The combination was relatively well tolerated in this heavily pre-treated cohort. The 3 drug regimen demonstrated a sufficient risk reduction to warrant further investigation. We propose molecular profiling on tumor samples that are available from a subset of this cohort.
BAP1 Is a Novel Target in HPV-Negative Head and Neck Cancer
Authors: Xiyou Liu, Manish Kumar, Liangpeng Yang, David P. Molkentine, David Valdecanas, Shiying Yu, Raymond E. Meyn, John V. Heymach, Heath D. Skinner
Journal: Clinical Cancer Research (2017)

Purpose: This study examined the potential role of the nuclear deubiquitinating enzyme BRCA1-associated protein-1 (BAP1) in radioresistance in head and neck squamous cell cancer (HNSCC).Experimental Design: We overexpressed, knocked down, and rescued BAP1 expression in six HNSCC cell lines, three human papillomavirus (HPV)-negative and three HPV-positive, and examined the effects on radiosensitivity in vitro and in an HNSCC mouse xenograft model. Radiosensitivity was assessed by clonogenic cell survival and tumor growth delay assays; changes in protein expression were analyzed by immunofluorescence staining and Western blotting. We also analyzed The Cancer Genome Atlas HNSCC database to test for associations between BAP1 expression and outcome in patients.Results: Overexpression of BAP1 induced radioresistance in both cell lines and xenograft models; conversely, BAP1 knockdown led to increased ubiquitination of histone H2A, which has been implicated in DNA repair. We further found that BAP1 depletion suppressed the assembly of constitutive BRCA1 foci, which are associated with homologous recombination (HR), but had minimal effect on γ-H2AX foci and did not affect proteins associated with nonhomologous end joining, suggesting that BAP1 affects radiosensitivity in HNSCC by modifying HR. Finally, in patients with HNSCC, overexpression of BAP1 was associated with higher failure rates after radiotherapy.Conclusions: BAP1 can induce radioresistance in HNSCC cells, possibly via deubiquitination of H2Aub and modulation of HR, and was associated with poor outcomes in patients with HNSCC. BAP1 may be a potential therapeutic target in HNSCC. Clin Cancer Res; 24(3); 600-7. ©2017 AACR.
P3.16-005 Outcome, Mortality and Morbidity after Lung Cancer Thoracic Surgery
Authors: F. Gradica, A. Cani, L. Lisha, D. Argjiri, F. Kokiqi, F. Gradica, I. Skenduli, E. Shehaj, V. Rexha, D. Lala
Journal: Journal of Thoracic Oncology (2017)
ACTR-06. DOSE DENSE TEMOZOLOMIDE (TMZ) AS INITIAL TREATMENT FOR HIGH-RISK OLIGODENDROGLIAL TUMORS: LONG-TERM RESULTS OF A PHASE II AINO (ITALIAN ASSOCIATION FOR NEURO-ONCOLOGY) STUDY
Authors: Riccardo Soffietti, Alessia Pellerino, Andrea Pace, Carmine Carapella, Cristina Dealis, Manuela Caroli, Marina Faedi, Lorenzo Bello, Roberta Rudà
Journal: Neuro-Oncology (2017)

High-risk low grade gliomas (LGGs) are characterized by either incomplete resection or progression following observation with MRI. Temozolomide (TMZ) alone after surgery represents an option to delay radiotherapy and risk of cognitive impairment. Thus far, the efficacy of dose dense TMZ in LGGs is not well known. Between 2006 and 2010 a single arm phase II study on 60 patients with high risk WHO grade II oligodendroglioma or oligoastrocytoma, age ≥ 18 years, KPS ≥70, measurable tumor on FLAIR MRI and absent or mild enhancement was performed. Primary endpoint was response rate according to RANO criteria and secondary endpoints were seizure control, progression-free survival (PFS), and overall survival (OS). Median number of TMZ cycles was 11 (2–18) with median follow-up of 64 months (7–112). Response consisted in PR 23/60 (38%), MR 12/60 (20%), SD 21/60 (35%), and PD 4/60 (7%). A significant seizure reduction was observed in 34/39 patients (87%) with maximal reduction either observed earlier than MRI or associated with a stable radiological disease. Median PFS was 40 months with 32% of patients progression-free at 60 months. MGMT methylation was associated with higher response (p=0.002) and longer PFS (p=0.019). 1p-19q codeletion and IDH 1/2 mutations tended to be associated with both response and PFS. Thirty-one (51.7%) patients decreased dose dense TMZ, 8 (13.3%) switched to standard schedule, and 6 (10%) discontinued the drug. Median survival from start of TMZ and subsequent salvage treatments was 92 months. IDH 1/2 mutations were significantly associated with longer survival. Response and outcome of high risk oligodendroglial tumors following dose dense TMZ are similar to that observed in studies employing the standard regimen. MGMT methylation is a predictive factor for both response and PFS. This is the first trial investigating seizure control as a secondary endpoint.
STEM-27. HDAC3: THE UNIVERSAL TARGET FOR GLIOBLASTOMA?
Authors: Emily Salt, Matthew Humphries, Ruth Morton, Ronald Grigg, Anke Brüning-Richardson
Journal: Neuro-Oncology (2017)

Histone deacetylase inhibitors (HDACi) are increasingly investigated as potential therapeutics in various cancers, including the most common brain malignancy, glioblastoma multiforme (GBM). The compound MI-192 has demonstrated selective inhibition of subtypes HDAC2 and 3, reportedly involved in tubulin acetylation and mitosis which drive migration and proliferation. The anti-migratory and anti-proliferative activity of MI-192 was investigated at two different concentrations (1,10 µM) in 3D invasion assays with spheroids developed from tumour core and edge cell populations of the patient-derived glioblastoma cell line GBM40. In addition, data was also generated using 2D scratch wound assays and immunofluorescence staining for Ki67 (proliferation), Nestin and SOX2 (stemness), Cleaved caspase 3 (apoptosis), HDAC 2 and 3 expression. GBM40 core and edge cell tumour populations displayed distinct phenotypes and differential cell marker expression levels. In 2D assays core-derived cells proliferated in close proximity to one another whereas edge cells displayed an invasive phenotype with individual lamellopodia and focal adhesions. SOX2 and nestin expression were altered in both core and edge-cell populations in response to HDAC inhibition, with both markers displaying upregulated expression in edge-derived cells. Core cells displayed significantly decreased SOX2 expression levels at 10µM MI-192. 3D spheroids increased in core area size and demonstrated decreased migration at 1µM concentrations, with the reverse occurring at 10µM. This study supports the idea that there are two distinct stem cell populations mediated via SOX2 and nestin, which predominate at specific sites within the tumour cell subpopulations. MI-192 may be a potential therapeutic for the clinical management of GBM affecting tubulin acetylation, SOX2 and nestin expression. This activity appears concentration dependent, inducing a proliferative and less invasive state at low concentration, potentially promoting greater tumour susceptibility to radiotherapy. Further studies are required to determine the in vivo effects of this compound in combination with radiation.
EXTH-66. GLIOBLASTOMA CELLS FROM A PATIENT POST-TUMOR TREATING FIELDS (TTFIELDS) THERAPY ARE SENSITIVE TO TTFIELDS IN VITRO
Authors: Sharon K Michelhaugh, Sam Kiousis, Sandeep Mittal
Journal: Neuro-Oncology (2017)

Brain metastasis (BM) are the most common type of brain tumor with an estimated incidence of 200,000-400,000/yr. in the US alone.BM are also the most common indication for stereotactic radiosurgery (SRS).However, while SRS is highly effective in achieving local control, the incidence of both local recurrence and radiation necrosis (RN) is increasing as treatment for primary systemic cancers improves.Among the challenges at the time of apparent imaging recurrence is differentiating "true" recurrence of BM from RN.Since conventional imaging is not always reliable for this, many patients must undergo surgical biopsy or resection due to this uncertainty.Here, we demonstrate the utility of the novel biomarker Vanin-2 (VNN2) combined with expression of MHC Class II molecule HLA-DR on CD14+ cells in order to differentiate recurrent BM from RN.Our preliminary data indicate that presence of Mo-MDSC is significantly increased in BM compared to RN (49% vs 4%, p=0.005).In contrast, VNN2 expression on CD14+ in BM is decreased compared to RN (4.3% vs 36%, p=0.02).In order to further decrease overlap between outliers in each group of patients, we define the ratio of HLA-DR expression to VNN2 expression on CD14+ cells from as the DR-VNN Index or DVI.While a DVI >1 is considered BM (average= 15.5), a DVI<1 is considered RN (Average 0.07).This increases the receiver operator curve (ROC) and thus the reliability of the biomarker.These results suggest that the novel biomarker VNN2 in conjunction with HLA-DRneg/low on CD14+cells, could be useful to differentiate BM from RN using a minimally invasive blood sample.Thus, the DVI has the potential to serve as an inexpensive and non-invasive biomarker in helping to manage clinical care.Further studies are indicated.
NIMG-91. RADIOMIC ANALYSIS OF PSEUDO-PROGRESSION COMPARED TO TRUE PROGRESSION IN GLIOBLASTOMA PATIENTS: A LARGE-SCALE MULTI-INSTITUTIONAL STUDY
Authors: Srishti Abrol, Aikaterini Kotrotsou, Ahmed Hassan, Nabil Elshafeey, Anand Agarwal, Islam Hassan, Tagwa Idris, Kamel Salek, Nikdokht Farid, Carrie McDonald, Shiao-Pei Weathers, Naeim Bahrami, Samuel Bergamaschi, Ahmed Elakkad, Kristin Alfaro-Munoz, Fanny Moron, Jason Huse, Jeffrey Weinberg, Amy Heimberger, Raymond Sawaya, Ashok Kumar, John de Groot, Meng Law, Pascal Zinn, Rivka Colen
Journal: Neuro-Oncology (2017)

Treatment-related imaging changes are often difficult to distinguish from true tumor progression. Treatment-related changes or pseudoprogression (PsP) subsequently subside or stabilize without any further treatment, whereas progressive tumor requires a more aggressive approach in patient management. Pseudoprogression can mimic true progression radiographically and may potentially alter the physician’s judgment about the recurrent disease. Hence, it can predispose a patient to overtreatment or be categorized as a non-responder and exclude him from the clinical trials. This study aims at assessing the potential of radiomics to discriminate PsP from progressive disease (PD) in glioblastoma (GBM) patients. We retrospectively evaluated 304 GBM patients with new or increased enhancement on conventional MRI after treatment, of which it was uncertain for PsP versus PD. 149 patients had the histopathological evidence of PD and 27 of PsP. Remaining 128 patients were categorized into PD and PsP based on RANO criteria performed by a board-certified radiologist. Volumetrics using 3D slicer 4.3.1 and radiomics texture analysis were performed of the enhancing lesion(s) in question. Using the MRMR feature selection method, we identified 100 significant features that were used to build a SVM model. Five texture features (E, CS, SA, MP, CP) were found to be most predictive of pseudoprogression. On Leave One Out Cross-Validation (LOOCV), sensitivity, specificity and accuracy were 97%, 72%, and 90%, respectively. 3D radiomic texture features of conventional MRI successfully discriminated pseudoprogression from true progression in a large cohort of GBM patients.
Induced Pluripotent Stem Cell (iPSC)–Derived Extracellular Vesicles Are Safer and More Effective for Cardiac Repair Than iPSCs
Authors: Marta Adamiak, Guangming Cheng, Sylwia Bobis-Wozowicz, Lin Zhao, Sylwia Kedracka-Krok, Anweshan Samanta, Elzbieta Karnas, Yu-Ting Xuan, Bozena Skupien-Rabian, Xing Chen, Urszula Jankowska, Magdy Girgis, Malgorzata Sekula, Arash Davani, Slawomir Lasota, Robert J. Vincent, Michal Sarna, Kathy L. Newell, Ou-Li Wang, Nathaniel Dudley, Zbigniew Madeja, Buddhadeb Dawn, Ewa K. Zuba-Surma
Journal: Circulation Research (2017)

Rationale: Extracellular vesicles (EVs) are tiny membrane-enclosed droplets released by cells through membrane budding or exocytosis. The myocardial reparative abilities of EVs derived from induced pluripotent stem cells (iPSCs) have not been directly compared with the source iPSCs. Objective: To examine whether iPSC-derived EVs can influence the biological functions of cardiac cells in vitro and to compare the safety and efficacy of iPSC-derived EVs (iPSC-EVs) and iPSCs for cardiac repair in vivo. Methods and Results: Murine iPSCs were generated, and EVs isolated from culture supernatants by sequential centrifugation. Atomic force microscopy, high-resolution flow cytometry, real-time quantitative RT-PCR, and mass spectrometry were used to characterize EV morphology and contents. iPSC-EVs were enriched in miRNAs and proteins with proangiogenic and cytoprotective properties. iPSC-EVs enhanced angiogenic, migratory, and antiapoptotic properties of murine cardiac endothelial cells in vitro. To compare the cardiac reparative capacities in vivo, vehicle, iPSCs, and iPSC-EVs were injected intramyocardially at 48 hours after a reperfused myocardial infarction in mice. Compared with vehicle-injected mice, both iPSC- and iPSC-EV–treated mice exhibited improved left ventricular function at 35 d after myocardial infarction, albeit iPSC-EVs rendered greater improvement. iPSC-EV injection also resulted in reduction in left ventricular mass and superior perfusion in the infarct zone. Both iPSCs and iPSC-EVs preserved viable myocardium in the infarct zone, whereas reduction in apoptosis was significant with iPSC-EVs. iPSC injection resulted in teratoma formation, whereas iPSC-EV injection was safe. Conclusions: iPSC-derived EVs impart cytoprotective properties to cardiac cells in vitro and induce superior cardiac repair in vivo with regard to left ventricular function, vascularization, and amelioration of apoptosis and hypertrophy. Because of their acellular nature, iPSC-EVs represent a safer alternative for potential therapeutic applications in patients with ischemic myocardial damage.
Elderly patients and metastatic soft tissue sarcomas (STS): a monoinstitutional experience
Authors: A. Comandone, A. Boglione, E. Giubellino, P. Bergnolo, O. Dal Canton, F. Garetto, D. Ottaviani, P. Pochettino, T. Mele, M.L. Sartori
Journal: Annals of Oncology (2017)