tbuckley/cabot-search huggingface dataset:
MA 20.14 Genotyping of Lung Cancer Using Cell-Free DNA (cfDNA) from Cytologic Supernatant (CSN)
Authors: N. Guibert, H. Tsukada, D. Hwang, T. Bale, E. Chambers, B. Ulrich, C. Paweletz, L. Sholl, G. Oxnard
Journal: Journal of Thoracic Oncology (2017)
3D Maskless Micropatterning for Regeneration of Highly Organized Tubular Tissues
Authors: Chi Ma, Tiejun Qu, Bei Chang, Yan Jing, Jerry Q. Feng, Xiaohua Liu
Journal: Advanced Healthcare Materials (2017)

Abstract Micropatterning is a widely used powerful tool to create highly ordered microstructures on material surfaces. However, due to technical limitations, the integration of micropatterned microstructures into bioinspired 3D scaffolds to successfully regenerate well‐organized functional tissues is not achieved. In this work, a unique maskless micropatterning technology is reported to create 3D nanofibrous matrices with highly organized tubular architecture for tissue regeneration. This micropatterning method is a laser‐guided, noncontact, high‐precision, flexible computer programming of machining process that can create highly ordered tubules with the density ranged from 1000 to 60 000 mm −2 and the size varied from 300 nm to 30 µm in the bioinspired 3D matrix. The tubular architecture presents pivotal biophysical cues to control dental pulp stem cell alignment, migration, polarization, and differentiation. More importantly, when using this 3D tubular hierarchical matrix as a scaffold, this study successfully regenerates functional tubular dentin that has the same well‐organized microstructure as its natural counterpart. This 3D maskless micropattern approach represents a powerful avenue not only for the exploration of cell–material interactions in 3D, but also for the regeneration of functional tissues with well‐organized microstructures.
IMMU-54. CD317 EXPRESSION IN HUMAN GLIOBLASTOMA: A TARGET FOR IMMUNOTHERAPY
Authors: Dorothee Gramatzki, Emese Szabo, Martin Gramatzki, Matthias Peipp, Michael Weller
Journal: Neuro-Oncology (2017)

Glioblastoma is the most common primary malignant brain tumor and has a poor prognosis. CD317 (HM1.24) is a transmembrane protein, overexpressed on plasma cells in multiple myeloma and in certain solid tumor types. Antibody drug conjugates receive increasing attention across oncology entities. Here, CD317 is evaluated as target for immunotherapy in glioblastoma, and the HM1.24-ETA' protein, a smal immunotoxin format with a CD317 single chain Fv (scFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA') is evaluated as therapy. In vivo, CD317 mRNA expression in human glioma of different grades and survival probabilities of glioblastoma patients based on CD317 mRNA expression were analyzed using the database of the Cancer Genome Atlas network (TCGA). CD317 protein expression was assayed by immunohistochemistry in a human tissue microarray (TMA). In vitro, we assessed CD317 mRNA expression by RT-PCR and CD317 protein levels by flow cytometry in 13 human glioblastoma cell lines. A cytotoxicity assay after treatment with HM1.24-ETA' immunotoxin was performed in human glioblastoma cell lines. Finally, HM1.24-ETA' was evaluated in the intracranial human LN-229 glioma xenograft nude mouse model. Interrogations from the TCGA database showed increased CD317 mRNA expression in human glioblastoma compared to lower grade gliomas. In the group of glioblastoma patients enhanced CD317 mRNA expression was associated with decreased probability of survival (p<0.001). CD317 protein levels correlated directly with the tumor grade of astrocytic gliomas in the TMA. CD317 was expressed heterogeneously on mRNA and protein levels in the tested cell-lines. HM1.24-ETA' induced cytotoxicity in CD317-positive glioblastoma cells in a concentration-dependent manner. HM1.24-ETA' prolonged survival compared to the control-toxin (anti-kappa-ETA') in the LN-229 xenograft nude mouse model (median survival: 39 days compared to 19 days; p=0.017). These data underline CD317 as a valuable target for immunotherapy by HM1.24-ETA' for glioblastoma patients.
QLIF-15. PERI-OPERATIVE RISK FACTORS FOR VENOUS THROMBOEMBOLISM DEVELOPMENT IN PATIENTS WITH MALIGNANT GLIOMA
Authors: Heather Wright, Daniel Douce, Chris Holmes, Alissa Thomas
Journal: Neuro-Oncology (2017)

The cumulative incidence of symptomatic venous thromboembolism (VTE) among patients with malignant gliomas (MG) is estimated to be as high as 36% during the course of therapy and confers a 2-fold increased risk of mortality. The aim of this study was to assess peri-operative risk factors that contribute to VTE. This retrospective chart review included patients ≥18 years diagnosed with MG (WHO grade 3-4) at the University of Vermont Medical Center from 2009 – 2016. Demographics, surgical details, histological diagnosis and grade as well as peri-operative labs were reviewed on 32 eligible patients. The Khorana scale, a commonly used scoring system to determine risk of VTE development in patients with cancer, was applied. Using SPSS, chi-square tests and univariate models were used to determine the relationship between peri-operative risk factors and VTE. Of the 32 patients followed in the study 10 developed VTE (31.2%). The average length of survival was 5.2 months after the development of VTE. Patients who had less than a gross total resection (biopsy or subtotal resection) had a significantly increased risk of developing VTE (p=0.05). The Khorana score had a sensitivity of 76.2% and specificity of 30.0% and was not a statistically significant predictor of VTE (p=0.336). Our single institution retrospective study suggests that residual tumor after surgical intervention places MG patients at higher risk for VTE. This study failed to validate use of Khorana score for predicting VTE risk in MG patients due to low specificity, suggesting that patients with MG may have risk for VTE that is unique from other patients with cancer. Because of the high rate of VTE and high prothrombotic potential of patients with MG, further studies are needed to determine whether prophylactic anticoagulant medications may help to reduce risk of VTE.
Risk of breast cancer recurrence remains for years after endocrine treatment ends, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Women treated for oestrogen receptor (ER) positive breast cancer have a persistent risk of recurrence for at least 15 years after being disease free with the current standard of five years’ endocrine therapy, a large meta-analysis of long term follow-up studies has reported.1

“This finding has implications for long term follow-up strategies and highlights the need for new approaches to reduce late recurrence,” the researchers, led by Hongchao Pan, from the University of Oxford, UK, said. They added, “The risk could be reduced by extending the duration of …
DDIS-20. FASN INHIBITION AS A POTENTIAL TREATMENT TO PREVENT METABOLIC ADAPTATION IN GBM
Authors: Aleksandra Gruslova, Adolfo Diaz Duque, Laura Caflisch, Stefano Tiziani, Alessia Lodi, Andrew Brenner
Journal: Neuro-Oncology (2017)

Response to antiangiogenic therapy (ie bevacizumab) in glioblastoma is mostly transient and without proven survival benefit. Acquired resistance to antiangiogenics is felt to be substantially driven by the hypoxic microenvironment. Tumor and matching sera from 12 patients having failed bevacizumab was performed by LCMS and NMR. Patient derived GBM neurosphere cultures were established using previously described methods and exposed to fatty acid synthase (FASN) inhibitor TVB-3166 at varying concentration in the presence of 20% or 2% oxygen. Evaluation of metabolic profiles from serum and tumor showed significant changes of number of fatty acids (including tricosanoic acid, carboceric acid, phosphatidylinositol 20:4, nonacosanoic acid, n-palmitoyl valine, ceramide 18:1/12:20), which was correlated with degree of hypoxic change. Continuous incubation in the presence of 200–800 nM TVB-3166 for 7–14 days leads to dose dependent inhibition of neurospheres formation and tumor cell death of patient derived GBM short term cultures. Given these findings, a pilot phase 2 study which evaluate the potential effectiveness and safety of TVB-2640 in combination with bevacizumab for patients with relapsed high-grade glioblastoma. This study will include an exploratory phase where patients will be randomized to either antiangiogenic therapy alone with bevacizumab, or the combination of bevacizumab and TVB-2640 for the first 28 days followed serum sampling and MRI. Fatty acid synthase inhibition is a potential strategy to overcome metabolic adaptation to antiangiogenics which will be explored in a recently initiated phase 2 study.
Proyecto Salm-gene: una colaboración europea para la impresión digital del ADN en la salmonelosis alimentaria
Authors: T M Peters, C Maguire, E J Threlfall, I. S.T. Fisher, O N Gill, A J Gatto
Journal: Eurosurveillance (2003)

El proyecto Salm-Gene llevo a cabo en Europa una valoracion de calidad externa del metodo de electroforesis en gel en campo pulsado (PFGE) para distinguir a los serotipos de los lisotipos. Se envio un conjunto de dieciseis cepas de S. Enteritidis a nueve laboratorios nacionales de referencia de salmonelas. Mediante un protocolo uniformizado, se compararon los perfiles PFGE obtenidos por los distintos centros. En casi todos los casos, se observo un 90% minimo de similitud entre los aislamientos analizados en distintos laboratorios europeos y, en general, la similitud fue g95%. Ello sugiere la posibilidad de reproducir los analisis PFGE y que, por lo tanto, pueden utilizarse como una valiosa herramienta de investigacion unida a los datos epidemiologicos.
ACTR-27. COMPLIANCE AND TREATMENT DURATION PREDICT SURVIVAL IN A PHASE 3 EF-14 TRIAL OF TUMOR TREATING FIELDS WITH TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Zvi Ram, Chae-Yong Kim, Garth A Nicholas, Steven Toms
Journal: Neuro-Oncology (2017)

Tumor treating fields (TTFields) are a physical anti-mitotic treatment modality characterized by their immediate mode of action and lack of a half-life. It has been shown previously that average monthly compliance with TTFields is correlated with overall survival in recurrent glioblastoma. A ≥75% compliance, i.e. an average daily use of at least 18h/d, has been suggested as a target for patients with recurrent glioblastoma when receiving TTFields as monotherapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields were applied together with temozolomide (TTFields/TMZ) and led to superior progression free (PFS) and overall survival (OS) compared to TMZ alone. Patients in the TTFields/TMZ arm received TTFields for a median of 8.2 months (95%CI 7.9–9.3), with 13%, 3%, 1% and <1% of patients on therapy at 2, 3, 4 and 5 years, respectively. We looked at different TTFields compliance bins and correlated them with PFS and OS compared to TMZ alone. The results show a threshold value of 50% average monthly compliance with TTFields is needed in order to obtain extension of both PFS (HR 0.70 95%CI 0.47–1.05) and OS (HR 0.67 95%CI 0.45–0.99) versus TMZ alone. A trend in favor of longer PFS and OS was seen with higher compliance bins (>90% compliance: PFS HR 0.54 95%CI 0.37–0.79; OS HR 0.52 95%CI 0.35–0.79). A Cox model controlling for gender, extent of resection, MGMT methylation status, age, region and performance status indicated compliance is independent of these factors (HR 0.78; p=0.031; for OS at compliance ≥75% vs <75%). In conclusion, in the EF-14 trial a compliance threshold of 50% with TTFields treatment was correlated with significantly improved outcomes. The results clearly show that the higher patients' compliance with TTFields, the better their outcomes. This effect was independent of other prognostic factors such as performance status, age and MGMT methylation.
Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel <i>MTOR</i> -Activating Mutation
Authors: Juan Francisco Rodríguez-Moreno, María Apellaniz-Ruiz, Juan María Roldan-Romero, Ignacio Durán, Luis Beltrán, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Jesus García-Donas, Cristina Rodríguez-Antona
Journal: Journal of the National Comprehensive Cancer Network (2017)

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.
RARE-10. MULTICENTER PILOT STUDY OF RADIO-CHEMOTHERAPY AS FIRST-LINE TREATMENT FOR ADULTS WITH MEDULLOBLASTOMA – THE NOA-07 TRIAL
Authors: Dagmar Beier, Martin Proescholdt, Torsten Pietsch, David Jones, Stefan M Pfister, Elke Hattingen, Linda Dirven, Ralf Lürding, Michael Weller, Rolf-Dieter Kortman, Ulrich Bogdahn, Peter Hau
Journal: Neuro-Oncology (2017)

Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radio-chemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective multicenter single-arm Phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. The NOA-07 trial combined cranio-spinal irradiation with vincristine, followed by eight cycles of cisplatin, lomustine and vincristine. Primary endpoint was the rate of toxicity-related treatment terminations after four chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Surrogate endpoints were evaluated in parallel. Thirty patients were evaluable. Each 50% percent showed classic and desmoplastic-nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in Non-WNT/Non-SHH. Four cycles of chemotherapy were feasible in the majority (n=21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first four chemotherapy cycles that may affect efficacy. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.
Adverse birth outcomes associated with Zika virus exposure during pregnancy in São José do Rio Preto, Brazil
Authors: M.L. Nogueira, N.R.R. Nery Júnior, C.F. Estofolete, A.C. Bernardes Terzian, G.F. Guimarães, N. Zini, R. Alves da Silva, G.C. Dutra Silva, L.C. Junqueira Franco, P. Rahal, C. Bittar, B. Carneiro, P.F.C. Vasconcelos, D. Freitas Henriques, D.M.U. Barbosa, P. Lopes Rombola, L. de Grande, A.F. Negri Reis, S.A. Palomares, M. Wakai Catelan, L.E.A.A. Cruz, S.H. Necchi, R.C.V. Mendonça, I.N. Penha dos Santos, S.B. Alavarse Caron, F. Costa, F.A. Bozza, A. Soares de Souza, C.C. Brandão de Mattos, L.C. de Mattos, N. Vasilakis, A.H. Oliani, D.C.M. Vaz Oliani, A.I. Ko
Journal: Clinical Microbiology and Infection (2017)
GENE-39. UNANTICIPATED GERMLINE CANCER SUSCEPTIBILITY MUTATIONS IDENTIFIED DURING ROUTINE NEXT GENERATION SEQUENCING OF PRIMARY CNS NEOPLASMS
Authors: Katharine Lord, Rachel Smith, Christina Boman, Gayle Patel, Srivani Thatikonda, Mark Burnett, James Waldron, Craig Kemper, Jeffrey S Weinberg, Morris D Groves
Journal: Neuro-Oncology (2017)

Tumor genomic profiling is routinely performed on primary brain tumors to identify somatic mutations. Such testing may also identify clinically significant germline mutations. Several syndromes (neurofibromatosis, Li Fraumeni, Von Hippel Lindau and Turcot) are well known causes of primary CNS neoplasms but there is limited data on other germline cancer susceptibility mutations in CNS tumor patients. After a somatic mutation was unexpectedly found to be germline, we interrogated our database of somatic CNS tumor mutations. This IRB approved retrospective study reviewed patients at the Texas Oncology-Austin Brain Tumor Center from May 2013 through April 2017. Tumors underwent genomic profiling using a commercially available test which evaluates 315 genes using next generation sequencing. Patients’ whose tumors carried a mutation which was concerning for a germline variant were tested further. Tumor genomic profiling was performed on 291 CNS tumor patients. Five patients were found to carry unexpected germline variants (1.7%). Two patients had glioblastoma: 1 BRCA2 pathogenic mutation, 1 MLH1 variant of uncertain significance; 2 anaplastic astrocytomas: 1 BRCA2 pathogenic mutation, 1 with pathogenic APC and ATM mutations; 1 atypical meningioma: 1 BRCA2 pathogenic mutation. Median age was 42.2 (range 33–53). As a result of the incidental findings, medical management was altered and testing of numerous family members was recommended. Complete tumor genomic profiles, pedigrees, and additional pending germline testing will be presented. In this series of primary brain tumor patients whose tumors were sequenced, unexpected germline variants were identified in the genes: BRCA2, MLH1, APC and ATM for an incidence of at least 1.7%. These results had life-saving implications for these patients and their families. This data is reasonably extrapolated to the brain tumor population at large and warrants further scrutiny of systematic approaches for identifying patients as candidates for germline testing based on tumor genomic profiling.
QLIF-35. EFFECTS OF INTEGRATIVE THERAPIES ON DISTRESS, PAIN, AND FATIGUE IN PATIENTS WITH PRIMARY BRAIN TUMORS: PRELIMINARY RESULTS FROM AN INTEGRATIVE MEDICINE REGISTRY
Authors: Laura Donovan, Angelica Rusilowski, Katherine Taromina, Teri Kreisl, Mary Welch, Andrew B Lassman, Elena Ladas, Fabio Iwamoto
Journal: Neuro-Oncology (2017)

Integrative medicine therapies are utilized by up to 80% of cancer patients for a variety of reasons, including symptom management and improvement in quality of life. There has been an increase in research with conflicting data on the efficacy of integrative therapies in cancer patients. In particular, there is a paucity of data regarding use of integrative therapies and their potential impact on symptoms and quality of life in patients with primary brain tumors. We report preliminary outcomes from an integrative medicine program available free of cost to neuro-oncology patients at Columbia University Medical Center (CUMC). 24 patients participated in an IRB-approved integrative therapies registry. Patients completed questionnaires pre- and post-integrative therapy sessions regarding symptoms including distress, pain, nausea and vomiting, and fatigue. There were 14 women and 10 men with a median age of 53.5 years (range 33-72 years) and 63% with a diagnosis of glioblastoma. 21 patients self-identified as non-Hispanic white (88%). The most common integrative therapies provided included acupuncture, acupressure, massage, and aromatherapy. Meditation, reiki, qi gong, and yoga were also offered. We compared pre- and post-intervention surveys for symptoms of distress (N=33 pre, 32 post), pain (N=20 pre, 15 post), and fatigue (N=15 pre, 8 post). The mean scores decreased for: distress (scale 0-10) from 5.79 to 1.84 (p <0.0001), pain (scale 0-4) from 2.15 to 0.47 (p<0.0001), and fatigue (scale 0-4) from 1.93 to 1.5 (p=0.17). These results suggest that integrative therapies may improve perceptions of distress and pain in patients with primary brain tumors. Additional research focusing on the effect and duration of specific treatments and their impact on overall quality of life is needed in this patient population.
RBIO-01. EXTRACELLULAR MILIEU IN RECURRENT HUMAN GLIOMAS: A REPERTOIRE FOR NOVEL DRUG DEVELOPMENT
Authors: Kshama Gupta, Terry Burns
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is uniformly fatal with a median survival of just over 1 year. Cranial radiation therapy (RT) alone or with Temozolomide is standard of care. Despite improved survival, the tumor inevitably recurs often more aggressively. The cause for such increased aggressiveness after RT is unclear. Our group previously established the transcriptional signature of radiated brain microglia, wherein 95% of the differentially upregulated genes pertained to inflammation, extracellular matrix (ECM), and mitochondria. Moreover, radiation has been shown to alter structure and maturation of ECM proteins. We hypothesized that changes in the radiated brain microenvironment may account for the observed aggressiveness of the recurrent tumor phenotype. To address this, nude mice were cranially radiated with 0, 10 or 20Gy radiation (N=10, mice per group). After 24hrs, mice underwent intracranial implantation of GBM cells from established xenograft, and tumor growth was monitored until moribund (~52 days) using MRI. At 1 month, microdialysis was performed on the contralateral hemisphere on at least 3 mice from each group, and perfusates were analyzed via unsupervised metabolomic profiling using liquid chromatography-mass spectrometry (LC-MS). After multivariate analysis, 100 metabolites were found to be differentially expressed between groups. Principle component analysis effectively separated groups 0Gy and 10Gy from 20Gy radiation. Among metabolites identified to be significantly upregulated after radiation (q ≤ 0.001), Allantoin, Creatinine and Glyceraldehyde, have been documented as intermediates of inflammatory pathways or neurodegeneration. Additionally, histologic evaluation of the brain sections revealed significant increase in overall tumor burden upon 20Gy radiation (p=0.03), %positive HE stained tumor area as 15% and 27% for 0Gy (N=9) and 20Gy (N=8), respectively; higher infiltrative behavior was confirmed by h-Lamin A+C, IF. These data suggest that changes in the extracellular milieu after RT may facilitate aggressive tumor recurrence. Harnessing metabolomic insights may reveal opportunities to attenuate the RT-associated aggressiveness of recurrent GBM.
P3.01-065 Advanced NSCLC with EGFR Mutations in Elderly Patients. Single-Center Experience
Authors: A. Artal Cortes, I. Torres, M. Álvarez, A. Comin, P. Felices, A. Nuño, I. Gurruchaga, D. Márquez, A. Viñaras, J. Hernando
Journal: Journal of Thoracic Oncology (2017)