tbuckley/cabot-search huggingface dataset:
Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma
Authors: Tanja Eisemann, Barbara Costa, Patrick N Harter, Wolfgang Wick, Michel Mittelbronn, Peter Angel, Heike Peterziel
Journal: Neuro-Oncology (2018)

Treatment options of glioblastoma, the most aggressive primary brain tumor with frequent relapses and high mortality, are still very limited, urgently calling for novel therapeutic targets. Expression of the glycoprotein podoplanin correlates with poor prognosis in various cancer entities, including glioblastoma. Furthermore, podoplanin has been associated with tumor cell migration and proliferation in vitro; however, experimental data on its function in gliomagenesis in vivo are still missing. Hence, we have functionally investigated the impact of podoplanin on glioblastoma in a preclinical mouse model to evaluate its potential as a therapeutic target.Fluorescence activated cell sorting, genome-wide expression analysis, and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9)-mediated deletion of podoplanin in patient-derived human glioblastoma cells were combined with organotypic brain slice cultures and intracranial injections into mice.We defined a malignant gene signature in tumor cells with high podoplanin expression. The increase and/or maintenance of high podoplanin expression in serial transplantations and in podoplaninlow-sorted glioblastoma cells during outgrowth indicated the association of high podoplanin expression and poor outcome. Unexpectedly, similar rates of proliferation, apoptosis, angiogenesis, and invasion were observed in control and podoplanin-deleted tumors. Accordingly, neither tumor growth nor survival was affected upon podoplanin loss.We report that tumor progression occurs independently of podoplanin. Thus, in contrast to previous suggestions, blocking of podoplanin does not represent a promising therapeutic approach. However, as podoplanin is associated with tumor aggressiveness and progression, we propose the cell surface protein as a biomarker for poor prognosis.
INNV-16. miRNA SIGNATURE DERIVED FROM GBM PLASMA EXOSOMES AS A DIAGNOSTIC BIOMARKER
Authors: Luz Cumba Garcia, Timothy Peterson, Ian Parney
Journal: Neuro-Oncology (2018)

Gliomas including glioblastoma (GBM) are the most common malignant brain tumors. Glioma extracellular vesicles (EVs), especially plasma exosomes, have biological effects such as mediating immunosuppression and contain signature tumor-specific cargo that could serve as liquid biopsies. Increasing interest in molecular biomarkers to determine patient prognosis in GBM has suggested that EV miRNA-based signatures may be able to predict progression-free and overall survival, differentiate normal donors from GBM patients, and distinguish true progression from treatment-related pseudo-progression. We have established a simple two-step technique, using density gradient ultracentrifugation (DGU), to isolate plasma exosomes from glioma patients and normal donors. One-step DGU (90 minutes/24,000 RPM) efficiently isolated exosomes from plasma, while a second DGU (16 hours/24,000 RPM) efficiently concentrated exosomes for subsequent cargo analysis, including miRNA signature analysis. Purification of total RNA, including miRNA, was performed on plasma exosomes from normal donors (n=8) and GBM patients (n=8) using the miRNeasy kit (Qiagen). Next generation short non-coding RNA sequencing samples was performed by Illumina HiSeq 2000 and revealed many differentially expressed miRNAs in GBM patients with high fold change/low false discovery rates compared to normal donor plasma exosomes. In order to test the diagnostic accuracy of the proposed technique for the differentiation of GBM patients and normal donors, ROC analysis was performed based on the top 30 differentially expressed miRNA samples. The area under the ROC curve (AUC; a figure of merit to determine the optimal miRNA signature) was 0.968. In addition, multiple novel miRNAs and other short non-coding RNA species (Y-RNA, piRNA, snoRNA) were found with some differential expression. In conclusion, miRNA sequencing from plasma exosomes shows marked differential miRNA expression between healthy donors and GBM patients. These findings as well as additional differentially expressed short non-coding RNA species suggest plasma EVs may serve as a robust platform to develop GBM liquid biopsies.
DDIS-20. NEW A6K BORON DRUG DELIVERY SYSTEM FOR CLINICAL APPLICATION OF BORON NEUTRON CAPTURE THERAPY (BNCT)
Authors: Hiroyuki Michiue, Asami Fukunaga, Atsushi Fujimura, Kazuyo Igawa, Hideki Matsui, Shuichi Furuya
Journal: Neuro-Oncology (2018)

In BNCT in GBM, one of the keys to success can depend on the boron compounds. The combination of BSH and BPA in clinical GBM BNCT showed good results and that meant the multi boron use in BNCT was one answer to next step of BNCT. In this time, we showed that the new self-assembling peptide DDS with BSH toward clinical application of BNCT. The self-assembling A6K peptide was found and reported by Dr. Shuguang Zhang, MIT in 1982. The A6K peptide showed self-assembling feature in water, and worked as drug delivery system of siRNA with only mixture. The A6K drug delivery system was clinically approved to breast cancer trial in Japan since 2015. We observed the complex of A6K and BSH with scanning electron microscope in different mixture ratio. Next, we checked the cell toxicity, measured intracellular boron concentration and observed BSH localization in mouse model. At first, we established the simple A6K/BSH complex making method, as just mixture the BSH and A6K water solution by itself. The BSH/A6K complex with different mixture ratio showed different shape and different diameter of complex in SEM image. The ideal range of particle size of DDS is 20nm to 200 nm, and ours’ complex diameter was about 40nm. Next, we administrated BSH/A6K complex to GBM cells and measured intracellular boron uptake. The concentration with BSH/A6K complex in U87 delta EGFR was 10 times or higher than that with BSH. Finally, we administrated BSH or A6K/BSH complex through mouse tail vein and got brain tumor sample after 12hr. The A6K/BSH mouse brain sample showed specifically accumulated BSH in tumor area. A6K peptide is clinical use in DDS and will spread various drug delivery tool for various clinical fields in future. Our A6K/BSH complex is very promising boron drug for next generation BNCT.
Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial
Authors: Mette S van Ramshorst, Anna van der Voort, Erik D van Werkhoven, Ingrid A Mandjes, Inge Kemper, Vincent O Dezentjé, Irma M Oving, Aafke H Honkoop, Lidwine W Tick, Agnes J van de Wouw, Caroline M Mandigers, Laurence J van Warmerdam, Jelle Wesseling, Marie-Jeanne T Vrancken Peeters, Sabine C Linn, Gabe S Sonke
Journal: The Lancet Oncology (2018)
PATH-20. ANAPLASTIC ASTROCYTOMA: WHY DOES SURVIVAL DIFFER SO MUCH FOR THE SAME HISTOLOGICAL GRADE?
Authors: Edward Goacher, Ryan Mathew, Oluwafikayo Fayeye, Aruna Chakrabarty, Carmel Loughrey, Richard Feltbower, Paul Chumas
Journal: Neuro-Oncology (2018)

Increasing knowledge and understanding of the molecular genetics driving both the occurrence and transformation of gliomas has led to a more discrete and objective classification of such tumours. Both phenotypic and genotypic variations now underpin their classification, and thus help to more accurately guide their clinical management. However, WHO Grade III Anaplastic Astroyctoma (AA) remains an unpredictable, heterogeneous entity; displaying a variable prognosis, clinical course and treatment response. AIMS: To examine additional measurable tumour characteristics that may delineate overall survival (OS) more predictably in AA. Data was collected on newly diagnosed cases of AA between 2003–2014, followed up for a minimum 3-years. Molecular information was obtained from case records and prospectively performed in cases where missing. Histological slides were manually examined for Ki67 proliferation index, cellularity and number of mitotic figures. Cox-regression and Kaplan-Meier analyses were used to assess OS. In total, 51 cases were included with an OS of 12months (range: 1 – 150months). Cumulative 3-year survival was 29.4%. Median age was 50years (range: 24 – 77years). Across the cohort, age, IDH1m status, oncological therapy and Ki67 were significant independent prognostic indicators on multivariate analysis (p<0.05). Median age in IDH1 wild-type (IDH1wt) tumours was significantly greater than IDH1 mutant cases (p<0.01). In cases demonstrating OS ≥3-years, Ki67 index, number of mitotic figures and percentage areas of ‘high cellularity’ were significantly reduced i.e. more characteristic of lower-grade/WHO Grade II glioma. Neither age nor Ki67 index had prognostic impact on IDH1wt cases. CONCLUSIONS: IDH1m status remains the most significant prognostic indicator amongst AA but Ki67 index has a significant independent prognostic value in AA. Number of mitotic figures and cellularity also offer valuable prognostic information. Further investigation utilising Ki67 quantification in standard tumour characterisation in histologically confirmed AA may aid in prognostication and inform precision medicine.
Inverse TGF-beta signaling between host and tumor induced by omega-3 and omega-6 fatty acids in COLO205
Authors: Nicole Kolenic, Trevor Fitcha, Ronald Pardini
Journal: Cancer Research (2007)

2074  Inflammation occurs at sites of foreign invasion or trauma as a result of the induction of cellular signaling hormones called cytokines, which are responsible for changes in tissue physiology, as well as the recruitment of immune cells to damaged areas. Colorectal cancer, the third most frequent cause of cancer death, is intrinsically linked with the inflammatory process. Previous studies have shown that treatment with NSAIDs have a tumor suppressing effect. Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine often seen functioning as a switch that can lead to either apoptosis or proliferation. Ras-mediated signaling through the TGF-beta pathway leads to proliferation, while the Smad-mediated pathway leads toward apoptosis. TGF-beta signaling has been best defined in mouse models where disruption can initiate or promote the neoplastic process.  Polyunsaturated fatty acids (PUFAs), particularly omega-3 and omega-6 fatty acids have been seen in epidemiological studies to have effects on cancer progression, with eicosapentaenoic acid (EPA), an omega-3 PUFA, decreasing tumor vascularity in vivo as well as decreasing pro-inflammatory cytokines. Previous studies in our lab, with athymic nude mice have found that diets with varying ratios of omega-3: omega-6 fatty acids have effects on tumor growth. Increased concentrations of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), have had a suppressive effect, while increased omega-6 fatty acids have had proliferative effects.  Recent feeding studies with varying fatty acid ratios have shown an inverse relationship between individual fatty acids and TGF-beta signaling. In high omega-3 PUFA diets, there is an increase within the splenocytes, a site of macrophage production in nude mice, in TGF-beta signaling, while the tumor shows a decrease. High omega-6 PUFA diets show the opposite results. Within the signaling pathway, phosphorylated JNK and p38, which are associated with Ras, are increased in omega-6 diets and decreased within omega-3 diets. Results suggest that omega-3 and omega-6 have markedly different effects on TGF-beta production and signaling that may turn the switch from apoptotic to proliferative based on diets with various PUFAs.
Abstract 017: Friends Make Children Less Sedentary but Neighborhoods Make Them More Active
Authors: Tracie Barnett, Melanie Henderson
Journal: Circulation (2018)

Background and Purpose: Sedentary behavior (SB) and physical inactivity are distinct constructs for which separate research and intervention paradigms may be warranted. To this end, we compared individual- and neighborhood-level risk factors of each among youth at risk of obesity. Methods: Data are from QUALITY, a cohort study of the natural history of obesity in Quebec, Canada. Baseline data were obtained in 2005-2008 when children were aged 8-10y (n=512 families). Activity level was measured using accelerometers at age 8-10y and again 2 years later at age 10-12y. At each time point, children were categorized as inactive if they did &lt;60 min/day of moderate to vigorous physical activity (PA) and as excessively sedentary if they recorded &lt;100 counts/min for &gt; 50% of the day. Children were required to have worn the device for at least 4 days and for at least 10 hours/day. Child-level factors included sex, sleep duration, and weekly frequency seeing friends; neighborhood-level factors included density of fast food outlets, convenience stores, and parks; school proximity, street connectivity, land use mix, disorder, social and material deprivation, and parental perceived safety. Separate logistic regression models were estimated for each of inactivity and excessive SB. We tested models using the identical set of baseline risk factors at both time points. Analyses were restricted to 413 children with complete data at age 8-10y, and to 283 children with complete data at age 10-12y. Models controlled for child’s obesity status, father and mother’s obesity status, and parental education. Results: At both time points, girls were 75% to 85% more likely to be inactive than boys, but were equally likely to be excessively sedentary as were boys. Also at both time points, each additional weekly outing with friends reduced the likelihood of being sedentary by 20%, but did not reduce the likelihood of being inactive. Only area-level disorder was associated with being excessively sedentary, and only in 10-12y olds; in contrast, several factors increased the likelihood of being inactive, including area deprivation at age 8-10y (OR: 1.7; 1.0-3.0) and perceived lack of safety at age 10-12y (OR: 2.8: 1.1-6.3). Moreover, the likelihood of being inactive decreased by 24% for each quintile increase in land use mix. Although obesity status in children was strongly associated with outcomes in all models, other determinants were unaffected by its inclusion in the models. Conclusions: Our findings suggest that physical inactivity and sedentary behavior are driven by largely distinct paradigms. Each of these may be impacted through increases in light PA. Although interventions need to target all spheres of influence, reducing physical inactivity may be more effectively mediated by features of the built environment, while leveraging social and peer groups may be more effective to reduce sedentary behaviors.
Deferred autologous stem cell transplantation in systemic AL amyloidosis
Authors: Richa Manwani, Ute Hegenbart, Shameem Mahmood, Sajitha Sachchithanantham, Charalampia Kyriakou, Kwee Yong, Rakesh Popat, Neil Rabin, Carol Whelan, Tobias Dittrich, Christoph Kimmich, Philip Hawkins, Stefan Schönland, Ashutosh Wechalekar
Journal: Blood Cancer Journal (2018)

High-dose melphalan with autologous stem cell transplantation (ASCT) can induce durable haematological and organ responses in systemic AL amyloidosis (AL). Stringent selection criteria have improved safety of ASCT in AL but most patients are transplant-ineligible. We report our experience of deferred ASCT in AL patients who were transplant-ineligible at presentation but had improvements in organ function after induction chemotherapy, enabling them to undergo ASCT. Twenty-two AL patients underwent deferred ASCT from 2011 to 2017. All had serial organ function and clonal response assessment. Organ involvement and responses were defined by amyloidosis consensus criteria. All patients were transplant-ineligible at presentation, predominantly due to advanced cardiac involvement. All received bortezomib-based therapy, with 100% haematologic response (86% complete response (CR)/very good partial response (VGPR)), enabling reversal of ASCT exclusion criteria. Patients underwent deferred ASCT for haematologic progression (45%) or consolidation (55%). There was no transplant-related mortality. Haematologic responses post-ASCT: CR 50%, VGPR 27%, PR 18%, non-response 5%. In all, 85.7% achieved cardiac responses. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 54 months. This selected cohort achieved excellent haematologic responses, organ responses, PFS and OS with deferred ASCT. If larger studies confirm these findings, this may widen the applicability of ASCT in AL.
ACTR-06. INITIAL RESULTS OF A PHASE I STUDY OF PROCASPASE ACTIVATING CCOMPOUND-1 (PAC-1) IN COMBINATION WITH TEMOZOLOMIDE FOR RECURRENT MALIGNANT GLIOMA
Authors: Martin Nicholas, Matthias Holdhoff, Richard Peterson, Oana Danciu, Jeffrey Wefel, Ted Tarasow, Paul J Hergenrother, Arkadiussz Dudek
Journal: Neuro-Oncology (2018)

Disruption of the intrinsic and extrinsic apoptotic pathways is a hallmark of neoplasia. Conversion of procaspase-3 to caspase-3 is a key reaction, as both pathways converge at this point. Procaspase activating compound -1 (PAC-1) catalyzes conversion of procaspase-3 to caspase-3 and induces apoptosis in tumor cells. Glioblastoma (GBM) is among the tumors that have high concentrations of procaspase-3 and low levels of caspase-3. PAC-1 has anti-tumor activity in several glioma cell lines in vitro. PAC-1 crosses the blood brain barrier and its addition to alkylating chemotherapy augments anti-tumor responses in in vivo rodent models and spontaneous canine gliomas. Taken together, these findings suggest PAC-1’s potential in glioma therapy. This dose-escalation phase I study to assesses the maximum tolerated dose (MTD) of PAC-1 administered daily for 21 days with TMZ, 150 mg/m2 for 5 days of each 28 day cycle in subjects with recurrent anaplastic astrocytoma (AA) or GBM. RANO criteria are used to assess response. A modified Fibonacci 3 + 3 design is used, expanding to 9 subjects at the MTD. Pharmacokinetics (PK) is assessed in each subject during cycle one. Secondary endpoints include pharmacodynamics and correlation of activity with procaspase-3 levels in tumor tissue. Neurologic toxicity, including cognitive function, is closely monitored throughout the trial. 6 subjects (all GBM) enrolled at the first dose level, 375 mg PAC-1/day. The PAC-1cycles administered ranged from 1–6 (mean = 3.2). All subjects left the study due to tumor progression. The best radiographic response was stable disease. The first cohort was expanded from 3 to 6 due to CTCAE grade 4 hepatotoxicity that resolved with dose reductions in both study drugs. An update of toxicity data and results of PK and tumor procaspase levels will be discussed.
IMMU-11. IDENTIFICATION OF GLIOMA-ASSOCIATED REGULATORY B CELLS AND EFFECTS OF RITUXIMAB IMMUNOTHERAPY
Authors: Catalina Lee Chang, Jason Miska, Aida Rashidi, Peng Zhang, Christina Appin, Ting Xiao, Aurora Lopez-Rosas, Yu Han, Maciej Lesniak
Journal: Neuro-Oncology (2018)

In the context of glioblastoma multiforme (GBM), immunotherapy remains a promising approach. However, the potent immunosuppression induced by GBM is one of the primary obstacles to finding effective immunotherapies. This immunosuppression is associated with high levels of immunosuppressive cytokines and a significant accumulation of both regulatory T cells (CD4+CD25+FoxP3+, Tregs) and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. Other actors of the immune system may also play a role in glioma immunobiology, such as B cells, known to infiltrate gliomas. From a total of 60 GBM samples, we observed that 40% of GBM samples scored positive for CD20+B-cell infiltration, presenting a discrete perivascular distribution. The current fundamental work aims to elucidate the phenotype and function of glioma-infiltrating B cells in two different glioma experimental model, GL261 and CT2A. Our results showed that glioma-associated B cells are a unique activated B-cell subset that produces immunoregulatory cytokines IL-10, TGFb and IL35; and inhibitory ligands PD-L1 and the polivirus receptor CD155. Glioma-associated Bregs are activated by MDSC and interact with activated CD8 T cells and strongly suppress their expansion and cytotoxic function, suggestive of their pro-tumorigenic function. In accordance, B-cell depletion therapy (anti-CD20; Rituximab) improved significantly animal survival. This work highlights the potential involvement of B cells in glioblastoma physiopathology and provides crucial information about the mechanisms by which gliomas is able to modulate B-cell immunity.
Efficacy of Eculizumab in Pediatric Patients with Paroxysmal Nocturnal Hemoglobinuria in the International PNH Registry
Authors: Álvaro Urbano-Ispizua, Austin G. Kulasekararaj, Marije Bartels, Christopher J. Patriquin, Britta Hoechsmann, Alexey A. Maschan, Amanda Wilson, Philippe Gustovic, Hubert Schrezenmeier
Journal: Blood (2018)
Abstract 16973: Prevalence, Determinants, and Impact of Target Lesion Calcification in Patients Undergoing Percutaneous Coronary Intervention With Newer Generation Drug Eluting Stents: Findings From a Large Multiethnic Registry
Authors: Robert S Copeland-Halperin, Usman Baber, Anitha Rajamanickam, Melissa Aquino, Swathi Roy, Jason C Kovacic, Pedro Moreno, Prakash Krishnan, Joseph Sweeny, Roxana Mehran, George Dangas, Annapoorna S Kini, Samin K Sharma
Journal: Circulation (2015)

Coronary calcification increases risk for adverse events in patients undergoing PCI with bare-metal or first-generation drug-eluting stents. Newer generation devices, however, are safer and more efficacious. Whether coronary calcification relates to risk in the newer generation DES era is unclear. We assessed the hypothesis that target lesion calcification in patients undergoing PCI with newer generation DES is associated with specific patient characteristics and clinical outcomes. We performed a retrospective analysis of a large, multiethnic cohort of patients undergoing PCI (n=14,054) with new generation DES at a single academic center between 2009 &amp; 2013. Coronary calcification was qualitatively assessed as none/mild, moderate or severe. Independent demographic, clinical and anatomic predictors of moderate/severe calcification were identified using logistic regression. Associations between coronary calcification and one-year MACE (death, MI or TVR) were examined using Cox modeling. Compared to patients with none/mild (n=11,530; 82.0%) those with moderate (n=1423; 10.0%) or severe (n=1101; 8.0%) coronary calcification were older, more often Caucasian, and had more complex target lesions and greater renal dysfunction. The strongest demographic, clinical and anatomic correlates of moderate/severe calcification were Caucasian race, renal dysfunction and left main target lesion. Unadjusted MACE rates among those with none/mild, moderate and severe calcification were 9.0, 14.7, and 17.9%, respectively (p&lt;0.001, Figure). After multivariable adjustment, hazard ratios (95% CI) for MACE associated with moderate and severe coronary calcification were 1.48 (1.27-1.72) and 1.72 (1.46-2.03), respectively. Despite the improved safety and efficacy profile of new generation DES, moderate to severe target lesion coronary calcification is not uncommon in the contemporary DES era and remains a strong and independent predictor of MACE after PCI.