tbuckley/cabot-search huggingface dataset:
NIMG-28. INCREASED MUTATION BURDEN (HYPERMUTATION) IN GLIOMAS IS ASSOCIATED WITH A UNIQUE RADIOMIC TEXTURE SIGNATURE IN MAGNETIC RESONANCE IMAGING
Authors: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya Matsuoka, Kristin Alfaro-Munoz, Nabil Elshafeey, Pascal Zinn, John de Groot, Rivka Colen
Journal: Neuro-Oncology (2017)

Increased mutation burden (hypermutation) has been reported in low and high-grade gliomas. Hypermutation is typically due to failure of DNA repair machinery such as mismatch repair (MMR) or disruption of DNA fidelity due to mutations in DNA polymerase genes (POLE and POLD). The incidence of hypermutation in high grade gliomas (mainly glioblastoma (GB)) occurs largely at recurrence and induces resistance to temozolomide therapy. Furthermore, defects in MMR genes in hypermutated GB can abolish and reverse the therapeutic effect of TMZ causing disease progression. Herein, we sought to identify an imaging-based signature for hypermutated gliomas using a radiomics-based approach. We retrospectively analyzed a total of 97 patients with primary gliomas from the University of Texas MD Anderson Cancer Center. Mutation status was determined post-biopsy (stereotactic/excisional) using Next Generation Sequencing (T200 and Foundation 1), and patients were grouped based on their mutation burden; 77 hypomutated (<30 mutations) and 20 hypermutated (>=30 mutations or <30 with MMR gene mutations). Radiomic analysis was performed on the conventional MR images (FLAIR and T1 post-contrast) obtained prior to tumor tissue surgical sampling; and a total of 2480 rotation-invariant radiomic features were extracted using: (i) the first-order histogram and (ii) grey level co-occurrence matrix. The Maximum Relevance Minimum Redundancy technique was used to select the most relevant radiomic features. ROC analysis and leave-one-out cross-validation (LOOCV) were used to assess the performance of the Support Vector Machine (SVM) classifier and AUC, Sensitivity, Specificity, and p-value were obtained. We found 100 radiomic features that can discriminate between hypermutated versus hypomutated gliomas, AUC 100% (CI: 96%-100%), Sensitivity 100%, Specificity 100%, p-value=1.8e-10. Increase in mutation burden seen in post-treatment glioma samples is associated with a unique radiomic texture signature on pre-sampling MRI and can be used to predict mutation burden status non-invasively.
Treatment and outcome for small bowel adenocarcinoma (SBA): a real life experience of two Italian centres
Authors: M. Occhipinti, A. Botticelli, C.E. Onesti, M. Ghidini, R. Righini, C. Pizzo, A. Milano, G. Tomasello, F.R. Di Pietro, L. Toppo, M. Ratti, R. Passalacqua, P. Marchetti, F. Mazzuca
Journal: Annals of Oncology (2017)
Issues of Awareness Related to Human Papillomavirus Infection Positivity Among US Adult Men
Authors: Mario R. Castellanos, Maria A. Farberov, Alia Kozlova
Journal: JAMA Oncology (2017)

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CBIO-16. INDUCTION OF AUTOPHAGY FOLLOWING TTFIELDS APPLICATION SERVES AS A SURVIVAL MECHANISM MEDIATED BY AMPK ACTIVATION
Authors: Anna Shteingauz, Yaara Porat, Moshe Giladi, Rosa Schneiderman, Tali Voloshin, Mijal Munster, Eilon D Kirson, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2017)

Tumor treating fields (TTFields) are an approved treatment modality for patients with glioblastoma. TTFields are delivered via noninvasive application of low-intensity, intermediate-frequency, alternating electric fields. Previous studies have shown that TTFields lead to increased granularity which is often associated with autophagy. In this study we evaluated the possible effect of TTFields on the induction of autophagy in glioma and NSCLC cells. Cells were treated with TTFields using the inovitro system. Cellular granularity was evaluated using flow cytometry. Autophagy was monitored by quantifying levels of lipidated Microtubule Associated Protein Light Chain 3 (LC3-II), in the presence and absence chloroquine (CQ) (lysomotropic agent inhibiting autophagy), using immunoblotting and immunofluorescence microscopy. Transmission Electron Microscopy (TEM) was used to visualize autophagosome-like structures. Western blot analysis was utilized to evaluate autophagy regulatory activity of the mammalian target of rapamycin (mTOR) through p70 S6 kinase1 (S6K1) and AMP activated protein kinase (AMPK). Flow cytometry analysis demonstrated that TTFields application leads to a significant increase in cellular granularity in all tested cell lines. Significant elevation in LC3-II levels was observed in treated cells using fluorescence microscopy, where punctate distribution of LC3-II was detected. Evidence of increased autophagic flux following TTFields application was also detected using immunoblotting analysis in presence of CQ. TEM micrographs demonstrated the presence of autophagy typical, autophagosome-like structures in TTFields treated cells. Combination of TTFields with CQ resulted in a significant dose dependent reduction of cell growth compared with TTFields treatment alone. Western blot analysis of cells after TTFields treatment revealed stimulation of AMPK signaling as well as activation of p70. Combined, these results suggest that cells upregulate autophagy in response to TTFields and that AMPK may serve as a key regulator of this process. This observation may open a window for sensitizing tumor cells to TTFields by using inhibitors of autophagy.
NCOG-05. TIME TO FUNCTIONAL AND COGNITIVE DECLINE IN A PHASE 3 TRIAL OF TUMOR TREATING FIELDS WITH TEMOZOLOMIDE VERSUS TEMOZOLOMIDE ALONE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Garth A Nicholas, Holger Hirte, Jacob Easaw, Thierry Muanza, David Roberge, David Mathieu, Marshall Pitz
Journal: Neuro-Oncology (2017)

Glioblastoma is a disease characterized by progressive decline in patients’ functional status and cognitive abilities. The EF-14 phase 3 trial demonstrated that adding TTFields to temozolomide (TTFields/TMZ) compared to temozolomide alone (TMZ) led to a significant increase in both progression free survival and overall survival of patients with newly diagnosed glioblastoma who had not progressed during their initial radiation therapy with TMZ. Time dependent differences in patients’ performance status and cognitive capabilities were protocol prespecified analyses. Time to deterioration (TTD) in performance status was measured using the Kaplan-Meier method considering a sustained decrease in Karnofsky performance score (KPS) of ≥10 points or death within 90 days of the last follow up an event. Patients without decline in KPS were censored at their last evaluation. TTD in cognitive function was measured using the Kaplan-Meier method considering a sustained decrease in Mini-Mental Status Score (MMSE) of ≥6 points or death within 90 days of the last evaluation of an event. Patients with a decline in MMSE of <6 points were censored at their last evaluation. TTD in KPS was similar to time to radiological disease progression and was significantly longer in patients treated with TTFields/TMZ than with TMZ alone (median 5.5 months vs 3.9 months; HR 0.84; p=0.0092). TTD in MMSE was longer than time to deterioration in KPS in both arms, and was significantly longer in patients treated with TTFields/TMZ than with TMZ alone (median 16.7 months vs 14.2 months; HR 0.81; p=0.012). Patients with compliance ≥75% with TTFields had significantly longer TTD in MMSE (p=0.0028) but not in KPS (p=0.652) compared to patients with compliance <75%. These results suggest that decline in performance status and cognitive capabilities are correlated with disease progression and extended by the addition of TTFields to TMZ.
HOUT-24. A MULTIPRONGED APPROACH TO IMPROVE PATIENT ACCESS TO CLINICAL TRIALS
Authors: Mathew Grubman, Marlon Garzo Saria, Jaya Gill, Najee Boucher, Annie Heng, MaDonna Johnson, Tiffany Juarez, Santosh Kesari
Journal: Neuro-Oncology (2017)

The strategic value of clinical trials in advancing cancer care and its direct benefits to patients, providers and practices cannot be overstated. While the needle has not significantly moved in terms of participation by adult patients with cancer and other neurological diseases, individual responses to therapy can lead to ad hoc post-trial analyses that may reveal factors that contribute to a favorable response. It is critically important to make clinical trials available and remove barriers to participation. To report the outcomes of developing a neuro-oncology clinical trial program that provides more options and facilitates earlier participation in clinical trials for patients with primary brain and central nervous system (CNS) cancers. Retrospective review of registry data from a single center. Patient data on prospectively enrolled cancer registry (2012-2016) from Providence Saint John’s Health Center were extracted and analyzed. Patients with primary brain and CNS cancers were included in the analysis Data from 409 patients were reviewed. There were a total of 205 primary brain and CNS cancers between 2012 and 2016, of which 132 (64.4%) were analytic cases and 73 (35.6%) were nonanalytic cases. There were 9 primary brain and CNS cancer trials available between 2012 and 2016, all opened after September 2015. A separate analysis of data after the initiation of the neuro-oncology clinical trial program revealed a total of 48 cases (23.4% of cases from 2012-2016) with 19 (39.6%) analytic cases and 29 (60.4%) non-analytic cases. The number of patients enrolled in clinical trials increased to 21 (44%) in 2016. Improving patient access to clinical trials not only provides direct benefit to patients but also adds strategic value to the organization.
First-line bevacizumab in combination with weekly paclitaxel for metastatic breast cancer: efficacy and safety results from a routine oncology practice analysis
Authors: A. Vannini, I. Meattini, R. Grassi, G.A. Carta, M. Perna, C. Becherini, P. Garlatti, V. Scotti, I. Desideri, P. Bonomo, L. Livi
Journal: Annals of Oncology (2017)
Don't forget the general practitioner
Authors: Michael Patrick Johnston, Iona Campbell, Judith Morris, Fiona Finlay
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: In a recent issue of Hepatology, Rush et al. reported a large retrospective cohort analysis regarding palliative care access for hospitalized patients.1 We read with interest the encouraging increase in utilization of palliative care specialist services. It was unsurprising that certain factors were associated with an increased rate of referral, not least among them the presence of hepatocellular carcinoma. In the United Kingdom, there has been a similarly identified need to improve access to palliative care for patients with liver disease.2 However, effective palliative care does not stop at the front door of the specialist center; it must extend into the community. Community care offers continuity for patients and has had success with simple interventions such as shared electronic patient records documenting an anticipatory care plan. This approach has been shown to improve important outcomes, including preferred place of final care for patients with liver disease.3 Although referral to specialist palliative care is often necessary, it is equally important to recognize the valuable anticipatory care planning and community palliative care already being delivered by patients’ personal physicians or general practitioners.
NIMG-92. VOLUMETRIC RESPONSE TO TTFIELDS IN NEWLY DIAGNOSED GBM
Authors: Christian Freyschlag, Johannes Kerschbaumer, Daniel Pinggera, Claudius Thomé
Journal: Neuro-Oncology (2017)

Optune TTField treatment is an established, non-invasive therapy for patients with newly diagnosed or recurrent glioblastoma (GBM). Treatment efficacy was evaluated demonstrating significant improvement of both, overall and progression free survival. For analysis, the MacDonald criteria were used in clinical practice as well as in the EF-14 trial. We performed a 3D volumetric analysis of patients with newly diagnosed GBM who underwent resection and chemoradiation plus TTFields additionally. Between February 2016 and April 2017, 14 patients were initiated with TTField treatment. Seven patients with a treatment duration of more than 3 months were available for analysis of volumetric response rates (newly diagnosed GBM, device usage over 60%). Patients included were using the device between 3 and 14 months. A 80% cutoff in device usage was arbitrary set as this corresponds to the recommended daily usage of over 18 hours (= 75% ADU). Contrast enhancing tumor on T1 imaging (MPRAGE, 1mm slice thickness) was assessed by segmentation and volumetric analysis. The median age was 48 years (range 17-68 years) at the date of treatment initiation. Median preoperative tumor volume was 20.3 cc (range: 1.12-58.6cc), postoperative volume was 6.3 cc (range: 0-14.2cc) and volume at time of analysis was 1.2 cc (range: 0-7.1cc). Average device usage (ADU) of these patients was 89.5%. The median change of volume from postoperative to posttreatment volume was 4cc (range: 0-7.1cc) in patients with a median device usage of over 80%; whereas in patients with lesser than 80%, the mean volume change was 2.2cc (range 0-3.2cc). TTFields are generally accepted and efficacious for treatment of GBM. Our analysis showed that the combination of radiation, Temozolomide and TTFields lead to a reduction in contrast enhancing tumor volume. The effect seems to be related to treatment duration.
NIMG-03. QUANTITATIVE MR MEASUREMENTS IN GLIOBLASTOMA PATIENTS: DIFFERENCE IN MEAN DIFFUSIVITY BETWEEN OPTUNE PATIENTS AND PATIENTS WITH ONLY STANDARD TREATMENT
Authors: Josef Vymazal, Radovan Zacek, Jan Sroubek, Jan Klener, Aaron Rulseh
Journal: Neuro-Oncology (2017)

Quantitative MR parameters, including those derived from diffusion imaging, may advance our knowledge regarding the biological characteristics of gliomas both in diagnostic and treatment settings. We evaluated whether any quantitative diffusion differences could be detected in glioblastoma patients treated with standard therapy plus TTFields (Optune™) and those treated with only standard therapy. Twelve participants with glioblastoma were subjected to surgical resection, radiotherapy and temozolamide. Six subjects were additionally treated with TTFields. All patients were followed by MRI every two months (range 210-1036 days) with standard imaging and diffusion tensor imaging until tumor progression. Progression-free survival (PFS) was significantly greater in the subgroup treated by TTFields (mean 848 days ± 369 SD, TTFields; 324 days ± 325, standard therapy). No group-wise difference was detected in initial mean diffusivity (MD) values in within the affected white matter near the resection cavity, however the linear regression slope describing MD in this region over serial measurements was higher in the subgroup treated by TTFields (5.43 ± 2.4 versus -3.77 ± 11.8). Our data suggest increasing MD in the affected white matter of glioblastoma patients is favorable, with PFS positively correlated with steeper regression slopes. Our patients treated by Optune had greater PFS in comparison to those that received standard therapy, and correspondingly MD increased in the affected white matter of these patients to a greater extent. In the group that received standard therapy, the increase was not as apparent and, if present, the slope was not as steep. Changes in MD likely reflect changes in tumor density in the white matter.
OA 15.04 Community-Based Lung Cancer Screening, Targeting High-Risk Ever Smokers in Deprived Areas of Manchester: an NHS Implementation Project
Authors: H. Balata, P. Crosbie, M. Evison, L. Yarnell, A. Threlfall, P. Barber, J. Tonge, R. Booton
Journal: Journal of Thoracic Oncology (2017)
Erratum: Corrigendum: Targeting cellular senescence prevents age-related bone loss in mice
Authors: Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir, Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava, Tamara Tchkonia, Merry Jo Oursler, James L Kirkland, Sundeep Khosla
Journal: Nature Medicine (2017)
PATH-41. IS ATRX IMMUNOCHEMISTRY USEFUL AS A SUBSTITUTE FOR ANALYSIS OF 1p/19q CODELETION IN GRADES II, III GLIOMAS?
Authors: Akane Yamamichi, Fumiharu Ohka, Kosuke Aoki, Hiromichi Suzuki, Masaki Hirano, Kazuya Motomura, Toshihiko Wakabayashi, Yukinari Kato, Atsushi Natsume
Journal: Neuro-Oncology (2017)

In the 2016 World Health Organization classification of tumors of the central nervous systems, genetic markers are included to define tumor entities in addition to histology. Especially in the lower-grade gliomas with IDH-mutant, status of chromosome 1p/19q codeletion is significant prognostic predictor, however its analysis methods such as Fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), or Multiplex Ligation-dependent Probe Amplification (MLPA) have limitations in routine clinical practice. Since ATRX mutation and 1p/19q codeletion are mutually exclusive, ATRX immunohistochemistry (IHC) is considered to be a potential substitute for analysis of 1p/19q codeletion. Nonetheless this issue has not been verified yet. ATRX gene abnormality has various mutation patterns, and few studies have investigated whether ATRX immuno-positivity is correlated with the ATRX mutation. We performed ATRX-IHC by using two antibodies in 78 grades II and III gliomas whose whole exome sequencing was performed including ATRX, IDH and 1p/19q statuses. Among 60 IHC positive cases, 8 (13.3%) were ATRX mutant, all of which have no characteristic mutational pattern. Four (22.2%) were ATRX wildtype in 18 IHC negative cases. Some ATRX wildtype but IHC negative cases received preoperative radiochemotherapy, but it does not affect the results. Describing the complex IHC expression of ATRX somatic mutations, our results reveal some caveats for the diagnostic practice.
Abstract 16519: Endothelium-Derived C-Type Natriuretic Peptide is a Critical Regulator of Angiogenesis and Vascular Remodelling
Authors: Aisah A Aubdool, Kristen J Bubb, Amie J Moyes, Jonathan P Drayton, Vedanta Mehta, Ian C Zachary, Janice Tsui, David J Abraham, Adrian J Hobbs
Journal: Circulation (2017)

Introduction:  Angiogenesis and vascular remodelling are complementary, innate responses to ischaemic cardiovascular events that restore tissue blood supply and oxygenation; the endothelium plays a critical function in these intrinsic protective processes. We have recently established C-type natriuretic peptide (CNP) as a fundamental endothelial signalling species that coordinates vascular homeostasis. Herein, we define a central (patho)physiological role for CNP in angiogenesis and vascular remodelling.   Methods:  The  in vitro  angiogenic activity of CNP was examined in human umbilical vein endothelial cells (HUVECs), pulmonary microvascular endothelial cells (PMEC) and aortic rings isolated from wild-type (WT), endothelium-specific CNP knockout (ecCNP KO) and global natriuretic peptide receptor (NPR)-C KO mice. These studies were complemented by  in vivo  experimentation exploring neovascularization following implantation of matrigel plugs and remodelling in response to carotid injury or unilateral hindlimb ischemia. In some studies, CNP was infused by osmotic minipump in an attempt to rescue any adverse phenotype.   Results:  Genetic or pharmacological targeting of CNP or NPR-C reduced the proliferative, migratory and 3D-tube forming capacity of HUVECs and PMECs  in vitro ; aortic sprouting was also reduced in ecCNP and NPR-C KO mice compared to WT.  In vivo , endothelial CNP and NPR-C KO mice exhibited greater medial hyperplasia and impaired re-endothelialisation following wire-induced vessel damage, and diminished  de novo  vascular network formation. Recovery of tissue perfusion, capillary density, and re-generation of muscle fibres following hindlimb ischaemia were impaired in ecCNP and NPR-C KO mice compared to WT littermates. This detrimental phenotype was reversed by pharmacological administration of CNP in ecCNP KO but not NPR-C KO mice.   Conclusion:  These data suggest that endothelial CNP plays a critical role in the vascular response to ischaemia and injury, promoting angiogenesis and remodelling. This beneficial, cytoprotective function is NPR-C-dependent and may prove an innovative approach to treating ischaemia cardiovascular disorders.
TMOD-21. CHARACTERIZATION OF PATIENT-DERIVED TUMOR SPHERES AND XENOGRAFTS FOR GLIOBLASTOMA
Authors: Noriyuki Kijima, Daisuke Kanematsu, Tomoko Shofuda, Ema Yoshioka, Yukako Handa, Shusuke Moriuchi, Masahiro Nonaka, Yoshiko Okita, Naohiro Tsuyuguchi, Junya Fukai, Yuichiro Higuchi, Hiroshi Suemizu, Yonehiro Kanemura
Journal: Neuro-Oncology (2017)

Patient-derived tumor spheres and xenografts are essential tools for translational research for malignant gliomas. However, only a subset of glioma samples are established as long-term sphere cultures and/or patient-derived xenografts. We aim to analyze the characteristics of patient-derived tumor spheres and xenografts. We tried primary sphere cultures by serum free medium containing EGF and bFGF from 56 glioma patient-derived samples (48 of grade 4, 4 of grade 3, and 4 of grade 2 tumors) and established long-term sphere cultures. We could establish 14 primary culture cell lines out of 48 glioblastoma samples (22.9% of glioblastoma) as long-term sphere cultures, and no long-term sphere culture was isolated from grade3 and grade 2 tumors. Next we investigated the genetic differences between the cell lines which were successfully established as long-term sphere cultures and those which were not. We found that cell lines with TERT promotor mutations are significantly established as long term-sphere cultures. TP53 mutation, EGFR amplification, and IDH1/2 mutation also might influence the success rate of long-term sphere cultures, but these factors were not statistically significant. We next investigated in vivo characteristics of glioblastoma patient derived xenograft models from these successfully established cell lines. We have injected these cell lines into NOD/Shi-scid IL2Rγ KO mouse and histopathologically analyzed characteristics of xenografts. Each xenograft well recapitulated histological features of original tumors and tumor cells remarkably invade through subventricular zone. These results suggest that long-term sphere culture is possible especially when the tumors are glioblastoma having TERT promotor mutations. Further technical improvement is needed to establish long-term sphere culture at higher percentages especially for glioblastoma samples without TERT promotor mutation. In addition, precise mechanism why tumor cells invade through subventricular zone is unknown, but these patient derived xenograft models are good models to analyze invasion and cancer stem cell properties of glioblastoma.