tbuckley/cabot-search huggingface dataset:
TMOD-18. THE PATIENT DERIVED XENOGRAFT NATIONAL RESOURCE: A COMPREHENSIVE COLLECTION OF HIGH-GRADE GLIOMA MODELS FOR PRE-CLINICAL AND TRANSLATIONAL STUDIES
Authors: Rachael Vaubel, Shulan Tian, Dioval Remonde, Mark Schroeder, Thomas Kollmeyer, Sen Peng, Ann Mladek, Brett Carlson, Daniel Ma, Gaspar Kitange, Lisa Evers, Paul Decker, Matthew Kosel, Michael Berens, Eric Klee, Andrea Califano, C David James, Daniel Lachance, Jeanette Eckel-Passow, Roel Verhaak, Erik Sulman, Nhan Tran, Caterina Giannini, Robert Jenkins, Ian Parney, Jann Sarkaria
Journal: Neuro-Oncology (2018)

Patient derived xenograft (PDX) models have shown great utility for pre-clinical and translational studies for a range of malignancies. We have established a comprehensive, publically available collection of 95 high-grade glioma flank PDX models. Viable PDX were derived from Glioblastoma, IDH-wildtype (n=91), Glioblastoma, IDH-mutant (n=2), Diffuse Midline Glioma, H3 K27M-mutant (n=1), and Anaplastic Oligodendroglioma (n=1) and include both primary (n=60) and recurrent (n=35) tumors. Comprehensive molecular characterization of PDX is ongoing and, to date, has included whole exome sequencing (WES, n=82), RNA-sequencing (n=40), and genome-wide methylation profiling (n=78) that included MGMT promoter, with data available in cBioPortal. PDX reflected the genetic characteristics of glioblastoma, with the majority harboring TERT promoter mutations, chromosomal gain +7, loss -10 and homozygous deletion of CKDN2A/B. EGFR alterations were frequent (~40%) and included amplification, point mutation, EGFRvIII, and other splice variants. Other common alterations, including amplifications of MET, CDK4, CDK6, MDM2, MDM4 and mutation of TP53, PTEN, NF1, RB1, PIK3CA, PIK3R1 were present at similar frequencies reported by TCGA, with the exception of PDGFRA alterations that were underrepresented in PDX. RNA-sequencing showed representation of each of the glioblastoma gene expression subtypes. To assess preservation of genetic features during xeongrafting, we performed WES on 20 matched patient tumors. The vast majority of genetic driver alterations were shared between patient and PDX, including EGFR, EGFRvIII, CDK4, MDM2, and MET amplifications. In 3 PDX, subclonal selection events were observed, including amplifications of MYCN, CDK6 and an EGFR splice variant, as well as selection against PDGFRA amplification. Overall, our large panel of PDX models reflects the genetic heterogeneity of glioblastoma and largely preserves the genetic features of the primary patient tumors. The PDX National Resource is a powerful tool for neuro-oncology research, with all PDX models and genomic data openly available (http://www.mayo.edu/research/labs/translational-neuro-oncology/mayo-clinic-brain-tumor-patient-derived-xenograft-national-resource).
Reduced expression of SMAD4 Influences on the Progression and Metastasis in Colorectal Adenocarcinoma
Authors: Kang Hong Lee, Seung Sam Paik, Ho Sung Yoon
Journal: Cancer Research (2008)

993  Background: SMAD4 gene is a tumor suppressor that is critical for transmitting signals from transforming growth factor-beta and is associated with cross-talk of signal pathways. We investigated the expression of SMAD4 to evaluate the role of SMAD4 in the development and progression and to assess the clinical values after surgery in colorectal adenocarcinomas. Methods: Immunohistochemistry for SMAD4 was performed on the tissue microarray of 429 colorectal adenocarcinomas. Results: Two hundred three of 429 cases (47.3%) were positive and 226 cases (52.7%) were negative for SMAD4 expression. 2/10 (20.0%), 15/39 (38.5%), 68/114 (47.2%), 111/190 (58.4%), 30/46 (65.2%) cases were negative for SMAD4 expression in AJCC stage 0, I, II, III, IV, respectively. 138/226 (61.1%) of SMAD4 negative cases and 90/203 (44.3%) of SMAD4 positive cases had lymphatic metastasis (p=0.001). 148/226 (65.5%) of SMAD4 negative cases and 91/203 (44.8%) of SMAD4 positive cases had lymphovascular invasion (p 0.05). Among age, sex, serum CEA level ( 6), tumor location (colon vs. rectum), differentiation (WD vs. MD vs. PD), lymphovascular invasion, stage (I vs. II vs. III vs. IV), serum CEA level and stage were significant prognostic factors on a Cox regression analysis (p=0.03, p=0.002, respectively). Recurrence patterns (local, hematogenous, and lymphatic recurrence) were not different between SMAD4 positive cases and negative cases. However time to recurrence were significantly earlier in SMAD negative cases (21.0±17.4 months) than that of SMAD4 negative cases (33.2±30.3 months) (p=0.0183). Conclusions: The results suggest that the loss of SMAD4 expression is an early event in development of tumor and influence on tumor progression and metastasis in colorectal adenocarcinomas. However, SMAD4 expression has no prognostic value after surgery in colorectal adenocarcinomas.
Could artificial intelligence make doctors obsolete?
Authors: Jörg Goldhahn, Vanessa Rampton, Giatgen A Spinas
Journal: BMJ (2018)

Machines that can learn and correct themselves already perform better than doctors at some tasks, says <b>Jörg Goldhahn</b>, but <b>Vanessa Rampton</b> and <b>Giatgen A Spinas</b> maintain that machines will never be able to replicate the inter-relational quality of the therapeutic nature of the doctor-patient relationship
HOUT-04. DEMOGRAPHIC PROFILES, MANAGEMENT AND CLINICAL OUTCOMES OF GLIOBLASTOMA PATIENTS TREATED AT ST. LUKE’S MEDICAL CENTER- PHILIPPINES
Authors: Roy Allan Dominique Torcuator, Paul Vincent Opinaldo, Erickson Torio, Julette Marie Batara
Journal: Neuro-Oncology (2018)

Glioblastoma is a highly aggressive primary brain tumor and typically treated with maximal safe resection followed by concomitant radiation and temozolomide followed by 6 cycles of adjuvant temozolomide. We reviewed histologically documented glioblastoma cases seen and treated at our center from 2005 until 2017. Demographic data, treatments received, PFS and OS were collected. 105 GBM patients were treated with a median age of 45 and KPS 90. Fifty five percent (58/105) had gross total resection, 18% subtotal resection and 13% biopsy. Seventy percent (74/105) were treated with RT plus TMZ, 15 %(16/105) RT alone and 1 patient treated with TMZ alone. The most common adverse events are fatigue and somnolence. Median follow up is 10.5 months. Progression free survival (PFS) is 13.38 months while overall survival (OS) is 15.43 months. This is the first study done for glioblastoma patients in the Philippines treated after surgery with RT plus concomitant and adjuvant TMZ. The results are consistent with the published data.
<i>Lactobacillus plantarum</i> bacteriocin is associated with intestinal and systemic improvements in diet-induced obese mice and maintains epithelial barrier integrity <i>in vitro</i>
Authors: Dustin D. Heeney, Zhengyuan Zhai, Zach Bendiks, Javad Barouei, Alice Martinic, Carolyn Slupsky, Maria L. Marco
Journal: Gut Microbes (2018)

We investigated the Lactobacillus plantarum bacteriocin plantaricin EF (PlnEF) system for its contributions to L. plantarum mediated benefits in a mouse model of diet-induced obesity. C57BL/6J mice on a high-fat diet (HFD) were administered a rifampicin resistant mutant of L. plantarum NCMIB8826 (NICMB8826-R) or an isogenic ΔplnEFI mutant strain, LM0419, every 48 h for nine weeks. Mice fed wild-type L. plantarum, but not LM0419, reduced their consumption of the HFD starting three weeks into the study and exhibited an overall 10% reduction in weight gain. The responses were independent of glucose homeostasis, as both NCMIB8826-R and LM0419 fed mice had improved oral glucose tolerance compared to sham controls. Although bacteriocins have antibacterial properties, the ileal, cecal, and fecal microbiota and cecocolic metabolomes were unchanged between mice fed either wild-type L. plantarum or the ΔplnEFI mutant. Instead, only mice fed NCMIB8826-R showed an increased production of ZO-1 in ileal tissues. To verify a potential role for the plantaricin EF system in supporting intestinal epithelial function, synthesized PlnEF peptides were applied to Caco-2 cell monolayers challenged with TNF-α and IFN-γ. The combination of PlnE and PlnF were required to prevent sustained cytokine-induced losses to Caco-2 cell para- and transcellular permeability and elevated IL-8 levels. In conclusion, this study shows that probiotic L. plantarum ameliorates the effects of obesogenic diets through a mechanism that involves the plantaricin EF system and likely includes L. plantarum – induced fortification of the intestinal epithelium.
CBMT-28. THE PROSURVIVAL ROLE OF HEME OXYGENASE-1 AND ITS REGULATION BY EGFRvIII IN GLIOBLASTOMA: SURGICAL AND PHOTODYNAMIC THERAPY APPLICATIONS
Authors: Andrea Fontana, Michael Reinert
Journal: Neuro-Oncology (2018)

The extent of surgical resection of Glioblastoma Multiforme can be greatly improved using 5-aminolevulinic acid (5-ALA) induced fluorescence-guided surgery. Yet, the intensity of the 5-ALA induced fluorescence is heterogeneous and may vary between patients. We have previously determined that Heme Oxygenase-1 is strongly involved in the metabolism of Protoporphyrin IX (PpIX), the fluorescent metabolite of 5-ALA (Fontana et al. 2017). Noteworthy, our experiments have shown that the EGF-mediated activation of Epidermal Growth Factor Receptor (EGFR) and its constitutively active truncation version, EGFRvIII is able to significantly increase the expression of HO-1 in glioblastoma cells. We are now investigating the role of Heme Oxygenase-1 in glioblastoma progression and possible future implications for 5-ALA-based photodynamic therapy. We measured the effect of EGFR/EGFRvIII status on the downstream effect on Heme Oxygenase-1 (HO-1). 5-ALA induced fluorescence, cell proliferation and survival were measured by different techniques. Furthermore, effects of inhibition by Tin(IV)-Protoporphyrin (SnPP) or gene knockdown using small interfering RNA (siRNA) against HO-1were analyzed. A significant difference in fluorescence was observed in U87MG and U87EGFR (EGFR overexpression) compared to U87EGFRvIII (EGFRvIII overexpression). Treatment with EGF, but not TGF-α significantly reduced cellular fluorescence by promoting HO-1 transcription and expression in a concentration-dependent manner, and the effect was reversed by HO-1 inhibition. We show evidence that this effect is mediated by pAKT/NF-kβ pathway activation. Furthermore, inhibition of HO-1 activity was significantly associated with an increase in apoptosis and reduced cell proliferation and survival. CONCLUSION: In GBM cell lines, 5-ALA-induced fluorescence is variable, and modulated by EGFR/EGFRvIII pathway activity inducing HO-1. EGFRvIII was shown to induce higher levels of HO-1 and therefore reduced cellular fluorescence. Furthermore, HO-1 protein expression was associated with cell survival and treatment with HO-1 inhibitors may reverse its anti-apoptotic/pro-survival effect and be therefore a new tool in GBM treatment.
Echovirus type 6 transmission clusters and the role of environmental surveillance in early warning, the Netherlands, 2007 to 2016
Authors: Susana Monge, Kimberley Benschop, Loes Soetens, Roan Pijnacker, Susan Hahné, Jacco Wallinga, Erwin Duizer
Journal: Eurosurveillance (2018)

Background In the Netherlands, echovirus type 6 (E6) is identified through clinical and environmental enterovirus surveillance (CEVS and EEVS). Aim We aimed to identify E6 transmission clusters and to assess the role of EEVS in surveillance and early warning of E6. Methods We included all E6 strains from CEVS and EEVS from 2007 through 2016. CEVS samples were from patients with enterovirus illness. EEVS samples came from sewage water at pre-specified sampling points. E6 strains were defined by partial VP1 sequence, month and 4-digit postcode. Phylogenetic E6 clusters were detected using pairwise genetic distances. We identified transmission clusters using a combined pairwise distance in time, place and phylogeny dimensions. Results E6 was identified in 157 of 3,506 CEVS clinical episodes and 92 of 1,067 EEVS samples. Increased E6 circulation was observed in 2009 and from 2014 onwards. Eight phylogenetic clusters were identified; five included both CEVS and EEVS strains. Among these, identification in EEVS did not consistently precede CEVS. One phylogenetic cluster was dominant until 2014, but genetic diversity increased thereafter. Of 14 identified transmission clusters, six included both EEVS and CEVS; in two of them, EEVS identification preceded CEVS identification. Transmission clusters were consistent with phylogenetic clusters, and with previous outbreak reports. Conclusion Algorithms using combined time–place–phylogeny data allowed identification of clusters not detected by any of these variables alone. EEVS identified strains circulating in the population, but EEVS samples did not systematically precede clinical case surveillance, limiting EEVS usefulness for early warning in a context where E6 is endemic.
ATIM-08. A PHASE I TRIAL OF PEMBROLIZUMAB AND VORINOSTAT COMBINED WITH TEMOZOLOMIDE AND RADIATION THERAPY FOR NEWLY DIAGNOSED GLIOBLASTOMA (NCT03426891)
Authors: Solmaz Sahebjam, Peter Forsyth, Nam Tran, Sepideh Mokhtari, John Arrington, Michael Jaglal, Arnold Etame, James Liu, Melissa Wicklund, Tyra Gatewood, Robert Macaulay, Timothy Robinson, Michael Yu
Journal: Neuro-Oncology (2018)

A growing body of evidence indicates that epigenetic silencing of genes involved in antigen processing and immune recognition results in immune escape and resistance to immunotherapy. Pre-clinical experiments have shown that use of histone deacetylases inhibitors such as vorinostat can restore tumor immune recognition and synergize with anti-PD 1/PD-L1 antibodies. Moreover, vorinostat has radiosensitizing properties. This report describes an ongoing phase I trial of vorinostat in combination with an antibody against PD1 (pembrolizumab), radiotherapy and temozolomide (TMZ) in patients (pts) with newly diagnosed glioblastoma (GBM). METHOD: This study employs a standard 3 + 3 dose escalation design exploring 2 sequential dose escalation cohorts of vorinostat. Eligible pts are treated with concurrent radiotherapy (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) followed by 6 cycles of maintenance TMZ. Pembrolizumab (200 mg) is administered intravenously once every 3 weeks. Dose level 1 is consistent of vorinostat 200 mg/day orally on days 1–5 every week during radiotherapy and 300 mg/day orally 1 week on 1 week off after radiotherapy. At dose level 2, pts receive 300 mg of vorinostat on days 1–5 every week during radiotherapy and 400 mg/day orally 1 week on 1 week off after radiotherapy. Once the recommended phase II dose (RP2D) of vorinostat is determined, an additional 20 pts will be enrolled in an expansion safety cohort. The primary study objectives are to determine safety and the RP2D of vorinostat administered with above combination in pts with GBM. Secondary endpoints include determination of the 12 and 24 month survival rates and exploring tissue and blood biomarkers. As of June 4, 2018, enrollment to dose level 1 has been completed. So far no does limiting adverse event has been observed. Thrombocytopenia and fatigue are the most common adverse events. Updated safety and efficacy results will be presented.
NCMP-21. REAL-WORLD SURVEILLANCE DATA FOR TUMOR TREATING FIELDS AFFIRM THE TOLERABILITY OF TUMOR TREATING FIELDS FOR THE TREATMENT OF GLIOBLASTOMA IN THE UNITED STATES
Authors: David Tran
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields) are a non-invasive, anti-mitotic therapy for the treatment of recurrent and newly diagnosed glioblastoma (GBM) and were approved for each indication in the United States (US) in 2011 and 2015, respectively, based on efficacy and safety data from the EF-11 and EF-14 clinical trials). In both trials, the most common adverse effect (AE) associated with TTFields therapy were mild to moderate skin toxicity underneath the transducer arrays of the Optune device. US post-marketing surveillance data collected for recurrent and newly diagnosed GBM patients treated with TTFields were analyzed to assess the real-world safety profile of TTFields for GBM. A review of the clinical information for recurrent and newly diagnosed GBM treated with TTFields in the United States identified 6,494 patients. The safety data obtained from post-market surveillance in all 6,494 patients were analyzed to identify AEs based on the MedDRA body system (system organ class) preferred terms. Forty five percent (2,941/6,494) of GBM patients experienced at least 1 AE while receiving TTFields treatment. Patients reporting general AEs include: 9% electric sensations, 4% fatigue, 9% heat sensation and 5% pain reported pain in any location. Nervous system AEs included headache (6%) and seizure (8%). The most common AE were skin reactions that were reported by 1,807 patients (28%). CONCLUSIONS: Analysis of real-world safety data for TTFields treatment in the US did not reveal any new safety signals for TTFields in the treatment of recurrent or newly diagnosed GBM. The most common AE related to TTFields were skin irritation under the transducer arrays. Skin reactions can be managed with topical treatments and slight adjustment of the transducer arrays to minimize skin irritation. Analyses of post-marketing US safety data corroborate the tolerability of TTFields for GBM patients observed in the Phase 3 clinical trials.
MT-DADMe-ImmA: A novel MTAP inhibitor with potential for the treatment of human head and neck and prostate carcinoma
Authors: Idranil Basu, Grace Polanski, Chandan Guha, Vern Schramm
Journal: Cancer Research (2005)

603  The polyamine biosynthetic pathway is a therapeutic target for the treatment of cancer because cellular proliferation requires an increased level of polyamine biosynthesis. Methylthioadenosine (MTA) is a by-product of the reaction catalyzed by both spermidine and spermine synthases and the only means of metabolizing MTA in mammals is phosphorolysis by methylthioadenosine phosphorylase (MTAP). Inhibition of MTAP may cause feedback inhibition of polyamine synthesis. MethylthioDADMeImmucillinA (MT-DADMe-ImmA) is a chemically stable analogue for the proposed transition state of human MTAP and is a slow onset inhibitor with a dissociation constant of 86 pM. The effects of MT-DADMe-ImmA were examined in head and neck squamous cell carcinoma (HNSCC) cell lines (FaDu & SCC25), prostate carcinoma (PC3) and normal human fibroblast (GM02037) cell lines. The effect of drug [MTA (20 μM) + MT-DADMe-ImmA (1 μM)] was examined for cell survival (WST-1 assay), clonogenic survival, morphological analysis with Hoechst staining, cell cycle analysis by flow cytometry and apoptotic assays. Control cells were treated with the inhibitor (MT-DADMe-ImmA) alone or the substrate (MTA) alone. In contrast to controls, MT-DAD-MeImmA + MTA induced a significant G2/M arrest (60% as compared to 8% in untreated cells), followed by apoptosis in FaDu cells (30% in drug-treated vs 6% in controls) within 4-6 days. Furthermore, treatment with MTAP inhibitors induced significant mitochondrial damage as confirmed by DiOC6 staining in these cells. In contrast to FaDu cells, SCC25 and PC3 cells underwent significant growth inhibition only after 8-16 days of treatment. To determine whether the inhibition was selective for malignant cells, normal human fibroblast cells (GM02037) were treated with MT-DADMe-ImmA for several weeks. No cytotoxicity was observed. Thus, MT-DADMe-ImmA is a novel transition-state inhbitor of MTAP for the treatment of human head and neck and prostate carcinoma.
HOUT-36. INSTITUTIONAL COMPLIANCE WITH TUMOR TREATING FIELDS FOR GLIOBLASTOMA
Authors: Robin Bonomi, Jay Burmeister, Michael Dominello
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) is a relatively new therapeutic intervention, which uses alternating electric fields to deliver low intensity, intermediate frequency current to solid brain tumors, thereby inhibiting mitosis. In the EF11 Phase III study in recurrent glioblastoma patient compliance, stratified by over or under 18 hours/day, for 28 days conferred a variable median survival benefit of 7.7 vs 4.5 months. In this study we report our institutional compliance in efforts to elucidate long term, >28 day, patient compliance in a clinical setting. After IRB approval we reviewed eleven patient TTFields compliance histories with recurrent and newly diagnosed GBM (age mean 55 ± 9 years). All patients underwent resection, chemotherapy (temozolomide +/- bevacizumab), and radiation therapy prior to TTField treatment. Duration of device use, hours of use per day, and reason for device discontinuation were reviewed with time to progression (TTP) determined by RECIST criteria. 6 patients met the recommended compliance of >18 hours per day (average 19.7 ± 1.0 hours/day), while 5 patients did not (averaging 11 ± 5 hours/day). 10 of 11 patients used TTFields for more than 100 consecutive days, with an average of 165 ± 85 days (range = 50 to 426 days). Patients discontinued use for a variety of reasons; death, insurance issues, and transition to hospice services following disease progression. After the start of TTFields therapy, the median TTP was 5.5 months (range 2 to 39 months). 5 patients with the longest TTP (>6 months) averaged >19.5 hours/day of treatment. While, 4 patients with the shortest TTP (3 months) averaged 11 hours/day. In a traditional clinical setting, many patients maintained compliance of >18 hours/day for an average of 165 days. In summary, we demonstrate that outside the scope of a clinical trial, high compliance with this device is a realistic and achievable goal.
Abstract 20172: Increased Pulmonary-Systemic Pressure Ratio is Associated With Adverse Events in Advanced Heart Failure
Authors: Sula Mazimba, Sara Schubert, Jigna Solanki, Hunter Mwansa, Alex Parker, Jamie L Kennedy, James Bergin, Mwenya Mubanga, Khadijah Breathett, Eliany Mejia-Lopez, Mohammad Abuannadi, Kenneth C Bilchick
Journal: Circulation (2017)

Increased Pulmonary-Systemic Pressure Ratio is Associated with Adverse Events in Advanced Heart Failure: Introduction: Concomitant presence of pulmonary hypertension in heart failure (HF) is associ...