tbuckley/cabot-search huggingface dataset:
Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial
Authors: Takamasa Kayama, Shinya Sato, Kaori Sakurada, Junki Mizusawa, Ryo Nishikawa, Yoshitaka Narita, Minako Sumi, Yasuji Miyakita, Toshihiro Kumabe, Yukihiko Sonoda, Yoshiki Arakawa, Susumu Miyamoto, Takaaki Beppu, Kazuhiko Sugiyama, Hirohiko Nakamura, Motoo Nagane, Yoko Nakasu, Naoya Hashimoto, Mizuhiko Terasaki, Akira Matsumura, Eiichi Ishikawa, Toshihiko Wakabayashi, Yasuo Iwadate, Shiro Ohue, Hiroyuki Kobayashi, Manabu Kinoshita, Kenichiro Asano, Akitake Mukasa, Katsuyuki Tanaka, Akio Asai, Hideo Nakamura, Tatsuya Abe, Yoshihiro Muragaki, Koichi Iwasaki, Tomokazu Aoki, Takao Watanabe, Hikaru Sasaki, Shuichi Izumoto, Masahiro Mizoguchi, Takayuki Matsuo, Hideo Takeshima, Motohiro Hayashi, Hidefumi Jokura, Takashi Mizowaki, Eiji Shimizu, Hiroki Shirato, Masao Tago, Hiroshi Katayama, Haruhiko Fukuda, Soichiro Shibui
Journal: Journal of Clinical Oncology (2018)

Purpose Whereas whole-brain radiotherapy (WBRT) has been the standard treatment of brain metastases (BMs), stereotactic radiosurgery (SRS) is increasingly preferred to avoid cognitive dysfunction; however, it has not been clearly determined whether treatment with SRS is as effective as that with WBRT or WBRT plus SRS. We thus assessed the noninferiority of salvage SRS to WBRT in patients with BMs. Patients and Methods Patients age 20 to 79 years old with performance status scores of 0 to 2-and 3 if caused only by neurologic deficits-and with four or fewer surgically resected BMs with only one lesion > 3 cm in diameter were eligible. Patients were randomly assigned to WBRT or salvage SRS arms within 21 days of surgery. The primary end point was overall survival. A one-sided α of .05 was used. Results Between January 2006 and May 2014, 137 and 134 patients were enrolled in the WBRT and salvage SRS arms, respectively. Median overall survival was 15.6 months in both arms (hazard ratio, 1.05; 90% CI, 0.83 to 1.33; one-sided P for noninferiority = .027). Median intracranial progression-free survival of patients in the WBRT arm (10.4 months) was longer than that of patients in the salvage SRS arm (4.0 months). The proportions of patients whose Mini-Mental Status Examination and performance status scores that did not worsen at 12 months were similar in both arms; however, 16.4% of patients in the WBRT arm experienced grade 2 to 4 cognitive dysfunction after 91 days postenrollment, whereas only 7.7% of those in the SRS arm did ( P = .048). Conclusion Salvage SRS is noninferior to WBRT and can be established as a standard therapy for patients with four or fewer BMs.
A paradigm of endothelium-protective and stent-free anti-restenotic therapy using biomimetic nanoclusters
Authors: Bowen Wang, Guojun Chen, Go Urabe, Ruosen Xie, Yuyuan Wang, Xudong Shi, Lian-Wang Guo, Shaoqin Gong, K. Craig Kent
Journal: Biomaterials (2018)
QOL-25. END-OF-LIFE EXPERIENCES OF CHILDREN WITH BRAIN TUMORS: PERSPECTIVES FROM A PANEL DISCUSSION
Authors: Katharine Brock, Erin Connelly, Brian Jackson, David Wrubel, Claire Mazewski
Journal: Neuro-Oncology (2018)

Brain tumors (BTs) have the highest mortality rate of all pediatric neoplasms. Patients with BTs have distinct constellations of symptoms including fatigue, headaches, seizures, cognitive impairment, loss of consciousness, speech impairments, swallowing difficulties, paralysis, incontinence, steroid-induced side effects, pain secondary to immobility, psychological effects, and changes to interpersonal interactions. Caring for children and young adults with BTs through the end-of-life (EOL) poses unique challenges for parents, caregivers, and providers alike. Using case examples of pediatric patients with high grade malignant tumors with poor prognoses such as diffuse intrinsic pontine glioma, high grade gliomas and recurrent medulloblastoma, we will explore the differing trajectories, decision-making points, and EOL experiences of children and the families who care for them. We will highlight cases where similar clinical scenarios have differing courses and outcomes. An expert panel including parents and clinicians in neuro-oncology, neuro-surgery, developmental therapeutics, palliative care, nursing, and ethics will provide various viewpoints, exhibiting opportunities for collaboration in care planning and debating points of contention. The panel’s discussions will focus on (1) shared decision making and ethical challenges around use of chemotherapy, radiation, steroid therapy, and surgical interventions such as resections and shunt placement, (2) early phase trial enrollment (both at one’s home institution or at another center), (3) advance care planning and the role of palliative care and/or hospice, (4) the use of complementary and alternative therapies and (5) the EOL experience for children and families choosing differing paths. Audience members will be allotted time to question the panel.
Comparison of Risk Stratification Models to Predict Recurrence and Survival in Pleuropulmonary Solitary Fibrous Tumor
Authors: Janani S. Reisenauer, Wadad Mneimneh, Sarah Jenkins, Aaron S. Mansfield, Marie Christine Aubry, Karen J. Fritchie, Mark S. Allen, Shanda H. Blackmon, Stephen D. Cassivi, Francis C. Nichols, Dennis A. Wigle, K. Robert Shen, Jennifer M. Boland
Journal: Journal of Thoracic Oncology (2018)
Enhanced susceptibility of cancer cells to oncolytic rhabdo-virotherapy by expression of Nodamura virus protein B2 as a suppressor of RNA interference
Authors: Donald Bastin, Amelia S. Aitken, Adrian Pelin, Larissa A. Pikor, Mathieu J. F. Crupi, Michael S. Huh, Marie-Claude Bourgeois-Daigneault, John C. Bell, Carolina S. Ilkow
Journal: Journal for ImmunoTherapy of Cancer (2018)

Antiviral responses are barriers that must be overcome for efficacy of oncolytic virotherapy. In mammalian cells, antiviral responses involve the interferon pathway, a protein-signaling cascade that alerts the immune system and limits virus propagation. Tumour-specific defects in interferon signaling enhance viral infection and responses to oncolytic virotherapy, but many human cancers are still refractory to oncolytic viruses. Given that invertebrates, fungi and plants rely on RNA interference pathways for antiviral protection, we investigated the potential involvement of this alternative antiviral mechanism in cancer cells. Here, we detected viral genome-derived small RNAs, indicative of RNAi-mediated antiviral responses, in human cancer cells. As viruses may encode suppressors of the RNA interference pathways, we engineered an oncolytic vesicular stomatitis virus variant to encode the Nodamura virus protein B2, a known inhibitor of RNAi-mediated immune responses. B2-expressing oncolytic virus showed enhanced viral replication and cytotoxicity, impaired viral genome cleavage and altered microRNA processing in cancer cells. Our data establish the improved therapeutic potential of our novel virus which targets the RNAi-mediated antiviral defense of cancer cells.
RADI-11. THREE CASES OF CLINICALLY SUSPECTED CAVERNOMAS FOUND TO HAVE VERY DIFFERENT PATHOLOGIES
Authors: Nicholas Pytel, Nicholas Harn, Shahriar M Salamat, Kristin Bradley, Raheel Ahmed, Bermans Iskandar, Diane Puccetti
Journal: Neuro-Oncology (2018)

Often radiological imaging is relied on for initial guidance as to the cause of different central nervous system symptoms such as headaches, neurological deficits, or other neurological changes. The clinical presentation is used along with the neurological imaging to provide the first steps for management in central nervous system lesions, including optimal timing for surgical procedures as indicated. We present 3 pediatric cases where the initial neurological imaging and clinical presentation appeared consistent with cavernoma or cavernous angioma, however, surgical pathology found that in all 3 cases, more concerning lesions were found beyond the vascular component. A 7 year old boy with obstructive hydrocephalus thought to be caused by vascular pineal cavernoma was later found to be a WHO Grade IV pineoblastoma. A 13 year old girl with headaches and double vision thought to have right midbrain cavernoma and evaluated at 3 separate institutions was found to have a WHO Grade II diffuse astrocytoma revealed by pathology. Finally, an 8 year old boy thought to have a pontine cavernoma was initially hospitalized for rehabilitation. When neurological symptoms shortly progressed and the lesion was found to double in size radiologically, surgical pathology shown a WHO Grade IV glioblastoma. We present the cases with associated neurological imaging and pathology following surgical biopsy or resection. Often conservative management is indicative for cavernomas based on imaging, but these cases did require surgical procedures given location and symptom control which was necessary to obtain correct diagnosis.
NSRG-18. IMPACT OF MOLECULAR SUBGROUP ON SURGICAL MANAGEMENT OF MEDULLOBLASTOMA
Authors: Andrea Carai, Alessandra Marongiu, Andrea Trezza, Alessandro De Benedictis, Silvia Cossu, Franco Randi, Evelina Miele, Antonella Cacchione, Giovanna Stefania Colafati, Francesca Diomedi Camassei, Angela Mastronuzzi, Carlo Efisio Marras
Journal: Neuro-Oncology (2018)

We present 47 consecutive patients operated at our Center for medulloblastoma in the last 5 years. Twenty five were males and mean age was 7 years. Eleven patients were infants. Surgery aimed at maximal safe resection in all cases. Molecular subgroup showed 7 WNT, 11 SHH, 14 Group 3, 15 Group 4. We tested a possible correlation between clinical variables relevant for surgery and molecular subgroup (Chi square test, significance = p<0.05). MRI suggested infiltration of the IV ventricle floor mainly in WNT (5/7) and SHH (7/11) tumors. In fact, Group 4 (11/15) and WNT (5/7) tumors were more frequently found to infiltrate brainstem at surgery. Overall, MRI showed low sensitivity (74%) and specificity (70%) in predicting brainstem infiltration. Clinical picture at onset showed a high frequency of hydrocephalus (40/47) independently of subgroup while cranial nerve deficit was more frequent in WNT (4/7) and significantly less frequent in Group 3 (3/14). Post-operative cranial nerve impairment consisted mainly in strabism (24/47) with a single case of facial weakness and were more frequently associated to Group 4 (12/25). Post-operative hydrocephalus requiring shunting was rare (5/47) and independent from molecular subgroup. Brainstem infiltration appeared to be the most relevant feature contributing to surgical complexity and neurological morbidity in medulloblastoma in our series, mostly in Group 4 and WNT tumors. Conversely, Group 3 showed a better neurological post-operative outcome. Further studies are warranted to better define the role of aggressive surgical resection in less aggressive molecular subgroups.
MBRS-49. USING SENSITIVE MAGNETIC RESONANCE IMAGING TECHNIQUES TO IMPROVE THE RISK STRATIFICATION OF PATIENTS WITH METASTATIC MEDULLOBLASTOMA
Authors: Christine Mitoko, Franziska Linke, Donald Macarthur, Henryk Faas, Beth Coyle
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) presents with metastasis in one-third of patients conferring a significantly poor prognosis. Unfortunately, current methods employed in risk stratification have limited sensitivity, with negative cerebrospinal fluid cytology and magnetic resonance imaging (MRI) in up to 50% of patients with histologically-proven metastases. Matrix metalloproteinases (MMPs) are enzymes secreted by tumour cells that can potentiate their dissemination. We hypothesised that the differential expression of MMP-2 and MMP-9, by a panel of sub-grouped MB cell lines, will correlate with their propensity to metastasise and that these differences are detectable using our synthesised 19Fluorine-MMP-MRI biosensor. Gelatin zymography, western blotting, and qRT-PCR were performed to determine MMP-2 and -9 functional activity, as well as protein and gene expression levels in 7 sub-grouped medulloblastoma cell lines. The same samples were imaged using our 19Fluorine-MMP-MRI biosensor. Our preliminary data shows that the expression of MMP-2 is upregulated in a recurrent group 4 MB cell line CHLA-01R MED compared to the matched isogenic primary CHLA-01 MED line at all levels. Additionally, an aggressive Group 3 cell line HD-MB03 repeatedly exhibited the highest levels of functionally active MMP-9 protein, and high MMP-2 gene expression at levels only comparable to the recurrent group 4 cell line. These findings suggest that MMP-2/-9 might be biomarkers for aggressive/metastatic MB. In order to achieve earlier, robust risk stratification of MB patients with disseminated disease, we aim to establish their potential as imaging biomarkers using our minimally-invasive, optimised 19F-MMP-2/- 9 MRI biosensor. Thereby, facilitating the prompt provision of personalised adjuvant therapy.
Publisher Correction: Thymosin α1 represents a potential potent single-molecule-based therapy for cystic fibrosis
Authors: Luigina Romani, Vasilis Oikonomou, Silvia Moretti, Rossana G Iannitti, Maria Cristina D’Adamo, Valeria R Villella, Marilena Pariano, Luigi Sforna, Monica Borghi, Marina M Bellet, Francesca Fallarino, Maria Teresa Pallotta, Giuseppe Servillo, Eleonora Ferrari, Paolo Puccetti, Guido Kroemer, Mauro Pessia, Luigi Maiuri, Allan L Goldstein, Enrico Garaci
Journal: Nature Medicine (2018)
ATRT-24. CHROMATIN SEGMENTATION IN ATRT REVEALS AN IMPORTANT ROLE FOR RESIDUAL SWI/SNF MEMBERS
Authors: Pascal Johann, Serap Erkek, Martina Finetti, Martin Hasselblatt, Daniel Williamson, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2018)

Although SMARCB1 mutations represent the only recurrent genetic aberration in atypical teratoid/rhabdoid tumors (ATRT), a comprehensive assessment of the epigenetic effect of SMARCB1 loss has not been attempted so far. To achieve this, we performed ChIP-sequencing for six histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary ATRTs, encompassing all three molecular subgroups of ATRT. Chromatin segmentation analyses revealed that across all three subgroups a high percentage of ATRT epigenomes resides in a quiescent state and active enhancer states are significantly underrepresented as compared to non-neoplastic brain. We validated these findings in a SMARCB1-reexpressing ATRT cell line and also found an overall deincrease of H3K27Ac and H3K27me3 upon SMARCB1 reexpression. Interestingly, by comparing the genome wide distribution of EZH2 and H3K27me3, we also identified classes of ATRT-specific active genes bound by EZH2, but lackingH3K27me3, pointing at a non-canonical role of EZH2 in gene activation. ChIP-Sequencing of SMARCA4 in these samples revealed that many of these „EZH2 only” genes display a high signal of of this protein. Many of these genes (such as e.g. CCND2) were downregulated upon knock-down of SMARCA4 in ATRT cell lines. Adding to the overall characterization of the epigenome, we have shown that a number of genes - despite being bound by EZH2- are maintained in an active state by residual SWI/SNF complex binding. This sheds new light on the role of residual SWI/SNFSMARCA4 still being present in AT/RT and elucidates a mechanism by which AT/RT keep important tumor-genes in an active state.
DIPG-21. EVALUATING THERAPEUTIC VULNERABILITIES IN DIPG USING AURORA KINASE INHIBITOR AS A NOVEL THERAPY
Authors: Liang Zhang, Andrew Bender, David Daniels
Journal: Neuro-Oncology (2018)

DIPG is one of the most aggressive pediatric brain tumors with no effective therapies. Majority of the midline high-grade pediatric gliomas carry somatic mutations of histone H3 resulting in the replacement of lysine 27 by methionine (K27M) and global loss of trimethylation on H3K27. In an effort to identify drugs for rapid clinical translation, we performed a rigorous high-throughput in vitro drug screen of FDA approved chemotherapeutics and epigenetic regulators. We have identified several major classes of drugs that potently reduce cell viability and proliferation of H3K37M tumors including the aurora kinase inhibitors (AKI). Using large cohorts from published data sets, we also confirmed a very distinct differential expression of Aurora Kinase (AK)-related genes in DIPG patients compared to normal brain and these results extended to our patient-derived H3K27M cell lines. Alisertib is a brain penetrant AKI that is orally available, with good safety and tolerability profile in children which will allow for rapid translation to the clinic. Importantly, gene expression of twelve AK related genes that we identified in our H3K27M cell lines correlated directly with sensitivity of that cell line to alisertib. We also identified an epigenetic mechanism of H3K27M trimethylation reprogramming with AKI treatment in H3K27M tumors. Finally we validated alisertib as a therapeutic target in animal models. The summation of these results supports the hypothesis that Aurora Kinases are critical for epigenetic reprogramming in H3K27M tumor cells and represents a targeted approach for treating tumors with this mutation.
Analysis of global factors associated with survival in esophageal squamous cell carcinoma: Our experience at Ramon y Cajal Hospital
Authors: A. Barquín García, J. Serrano Domingo, C. Saavedra Serrano, V. Albarrán Artahona, M. Villamayor Delgado, O. Martínez Saez, J. Molina Cerrillo, R. Martín Huertas, E. Corral de la Fuente, R. Ferreiro Monteagudo, M. Rodriguez Garrote, V. Pachón Olmos, M. Vaz, P. Reguera Puertas, C. Guillén-Ponce, A. Carrato, F. Longo Muñoz
Journal: Annals of Oncology (2018)

Introduction: Rates for esophageal squamous carcinomas (ESCC) have been steadily decreasing because of long-term reductions in tobacco use and alcohol consumption. However, ESCC is still a highly lethal malignancy and distant metastases to the liver, bone, and lung are seen in nearly 30% of patients. Moreover, the prognosis is poor, with al 5-year overall survival (OS) of 10 - 20%. In patients treated with curative intent, the cure rate currently approaches 40%, with the majority of recurrences develop within one year. Nevertheless, it seems that there are no clear prognostic factors or biomarkers established to date. Methods: We conducted an observational retrospective study. Patients with ESCC between 2000 and 2017 were identified, and data was collected for exploratory predefined variables including patient (age, weight, height, BMI, ECOG, tobacco and alcohol consumption, analytic parameters) and tumor characteristics (location, stage, grade), treatment procedures (chemotherapy, chemorradiotherapy (CRT) and surgery) and oncological outcomes. We analysed OS and relapse free survival (RFS) rates according to the presence of these factors. Univariate Cox regression analysis was performed and those variables which obtained a p<0.05 were incorporated in a multivariate model. Stata 13.1 was used to analyze the data. Results: 138 ESCC patients were identified: median age of 66 years; 87% were male; 62% located in the mid-esophagus; the majority were grade 2 (31%); 43% stage III and 35% stage IV; most patients were tobacco (91%) and alcohol consumers (62%). Treatments received: 51% chemoradiotherapy (CRT), 9% CRT + surgery, 10% chemotherapy (CT) and 12% radiotherapy (RT). Median follow up was 9.7 months and median OS was 11 months. In the univariate analysis for OS: ECOG, weight, height, platelets, leukocytes, neutrophils, grade, stage and treatment modality were prognostic. In the multivariate model: ECOG 0 (HR 0.44, p=0.039), stage IV (HR 4.28, p=0.05), treatment with RT (HR 0.21, p=0.001) and neutrophil count (HR 1.03, p=0.021) were seen as independent prognostic factors. Moreover, 89 patients (65%) presented as localized ESCC. Median RFS and OS were 16 and 21 months, respectively. In the univariate analysis for OS: ECOG, T, N and surgery were prognostic. In the multivariate model: ECOG 3 (HR 12.7, p=0.001), T4 (HR 9.22, p= 0.002) and N3 (HR 3.57, p=0.028) were identified as independent prognostic factors. Conclusion: The multivariate analysis did show some independent risk factors for OS in ESCC according to patient and tumor characteristics, treatment procedures and oncological outcomes.
Oncologic outcomes of elderly patients with localized esophageal cancer who underwent curative surgery compared with younger patients
Authors: H. Choi, S. Sung
Journal: Annals of Oncology (2018)

Introduction: The management of older patients with esophageal cancer can be quite challenging because they have multiple comorbidities and physiological changes associated with aging that may hinder their ability to receive and tolerate combined modality therapy. We investigated this study to determine the toxicity and oncologic outcome of elderly patients (> 65 years) with localized esophageal cancer who underwent curative surgery compared to younger patients (≤ 65 years). Methods: We performed a retrospective chart analysis from January 2010 to December 2016. A total of fifty-five esophageal cancer patients were included in this study. All patients received curative aimed surgery. Patients with locally advanced esophageal cancer received neoadjuvant chemoradiation at a dose of 50.4Gy in 28 fractions before surgery. Results: Elderly patients were 24 (43.6%) and younger patients were 31(56.4%). The median age was 57 years for the younger patient group and 70 years for the elderly group. pT stage, pN stage, and neoadjuvant chemoradiation did not show any difference between two groups (p = 0.206, 0.567, 0.137). The 3-year recurrence free survival rate was not significantly different between elderly group and younger group (48.3% vs. 47.0%, p = 0.361). The 3-year local recurrence free survival and distant metastasis free survival did not show any difference between two groups (local recurrence free survival: 51.4% vs. 53.7%, p = 0.636; distant metastasis free survival: 60.0% vs. 63.9%, p = 0.678). Conclusion: Elderly esophageal cancer patients with good performance status showed comparable recurrence-free survival compared with younger patients.