tbuckley/cabot-search huggingface dataset:
CSIG-22. MUTATIONAL HETEROGENEITY OF THE EGFR EXTRACELLULAR DOMAIN PROMOTES AN ONCOGENIC UNTETHERED TRANSITIONAL CONFORMATION AND THE POTENTIAL FOR GREATER THERAPEUTIC TARGETING IN GBM PATIENTS
Authors: Amy Haseley Thorne, Laura Orellana, Alison Parisian, Webster Cavenee, Frank Furnari
Journal: Neuro-Oncology (2016)

The epidermal growth factor receptor (EGFR) is both amplified and frequently mutated in glioblastoma (GBM). While downstream inhibition of EGFR signaling through small molecule tyrosine kinase inhibitors (TKIs) has shown little clinical efficacy, monoclonal antibody targeting is proving to be a promising alternative. The monoclonal antibody 806 (mAb806) specifically binds the most common EGFR mutant, EGFRvIII, as well as amplified WT-EGFR, but not EGFR expressed at low levels. The selectivity of mAb806 is thought to be due to its targeting a tumor-specific epitope of EGFR which is only accessible as the receptor transitions between an inactive tethered conformation to an active ligand-bound dimer. To address this question, we modeled several point mutations of the EGFR ectodomain (ECD) which naturally occur in GBM patients. Using molecular dynamics simulations we show that G63R and R108K expose the mAb806 epitope by way of their extreme flexibility at the domain I-II hinge region. In vitro analyses of these mutants reveals an increased ability to bind mAb806 in glioma cell lines. Furthermore, these point mutations and others were found to increase tumorigenicity in vivo. Examining downstream signaling pathways revealed similarities in signaling between the ECD deletion mutants EGFRvIII and EGFRvII while the individual point mutants R108K, G63R, A289V and G598V signal similarly to WT-EGFR. We go on to show that although treatment with a TKI before mAb806 increases binding to U87 parental and WT-EGFR expressing cells, and thus will likely prove to have increased toxicity in patients, forcing the kinase domain of EGFR into an active vs. inactive state had surprisingly different effects on mAb806 exposure based on its mutational status. Thus, the ECD mutants may be used as a tool to increase the understanding of how EGFR structure affects function and ultimately oncogenicity.
GENT-28. THE EPIGENETIC LANDSCAPE OF ATYPICAL TERATOID/ RHABDOID TUMORS REVEALS A REPRESSED METHYLOME AND EPIGENETIC SWITCHES AT SMARCB1 BINDING SITES
Authors: Serap Erkek, Pascal Johann, Kornelius Kerl, Martina Finetti, Marc Zapatka, Michael C. Fruehwald, Lukas Chavez, Amar Gajjar, Daniel Williamson, Martin Hasselblatt, Stefan M. Pfister, Marcel Kool
Journal: Neuro-Oncology (2016)

Even though SMARCB1 mutations are the only genetic aberrations in atypical teratoid / rhabdoid tumors (ATRT), we recently demonstrated that distinct molecular subgroups exist. However, the broad effects of SMARCB1loss on the epigenetic landscape of these three subgroups remain unclear. We performed ChIPsequencing for six active and repressive histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary AT/RT, encompassing all three subgroups. DNA-methylation and gene expression data were available for all cases and integrated into the analysis. The overall chromatin analysis, compared to non-neoplastic brain tissues, revealed that for all three subgroups a high percentage of the AT/RT genome is either in a quiescent or polycomb repressed state and a significantly lower percentage of the AT/RT genome is in an active enhancer state, suggesting a subgroup independent effect of SMARCB1loss in these tumors. There is, however, a clear difference between the subgroups regarding the distribution of specific enhancer and repressive marks. Surprisingly, we discovered a dual role of EZH2, not only associated with repressed chromatin, but also with active promoters. SMARCB1 ChIP-seq analyses in normal brain suggested that in AT/RT a transition from active chromatin states to either bivalent or repressed chromatin states at SMARCB1 binding sites takes place. Due to this switch at SMARCB1 binding sites, we detected several tumor suppressors transcriptionally repressed. These may play a role in AT/RT tumorigenesis. Our comprehensive study of histone marks in this gentically homogeneous but epigenetically heterogeneous disease enabled us to not only shed a light on the chromatin landscape of these tumors but also on the potentially tumorigenic consequences of SMARCB1 loss. In addition, the dual role of EZH2 in these tumors further enhances the importance of this molecule as a therapeutic target and underlines the importance of clinically targeting this molecule.
Abstract B10: Transcriptome analysis of mouse PDA subtypes
Authors: David Balli, Nicole Aiello, Robert Norgard, Jingyang Li, Amine Sahmoud, Ben Stanger
Journal: Cancer Research (2016)

Abstract Patients with Pancreatic Adenocarcinoma (PDA) often present with advanced stage disease including widespread metastasis and have dismal 5-year survival rates. The molecular mechanism promoting PDA progression and metastasis remain poorly understood. We have previously demonstrated that tumor cells undergo Epithelial-to-Mesenchymal Transition (EMT) in mouse models of PDA [Rhim et al., 2012]. EMT is a developmental process where cells loss epithelial characteristics and transdifferentiate into a mesenchymal-like state that is highly associated with increased invasion and metastasis. To better understand molecular mechanisms of PDA development and metastatic disease, we subjected tumors cells from a lineage labeled mouse model of PDA to RNA sequencing to identify global transcriptional changes. Interestingly, we discovered that there are at least two distinct subtypes of PDA based on transcriptome profiling. Comparison of gene expression profiles from mouse PDA subtypes to established subtypes from human PDA datasets [Collisson et al., 2011] revealed that mouse PDA is transcriptionally similar to the human disease. Differences in transcriptional profiling between PDA subtypes may dictate response to chemotherapeutics and metastatic competency. Citation Format: David Balli, Nicole Aiello, Robert Norgard, Jingyang Li, Amine Sahmoud, Ben Stanger. Transcriptome analysis of mouse PDA subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B10.
Regorafenib in patients with refractory metastatic pancreatic cancer. An open-label phase II study (RESOUND)
Authors: S. Bozzarelli, L. Rimassa, L. Giordano, S. Sala, M.C. Tronconi, M. Baretti, N. Personeni, T. Pressiani, A. Santoro
Journal: Annals of Oncology (2016)
Risk of prostate cancer mortality in men with an initial benign needle core biopsy set: a population based analysis with up to 20 years of follow-up
Authors: N. Klemann, J.T. Helgstrand, K. Brasso, B. Vainer, B.G. Toft, M.A. Røder, P. Iversen
Journal: Annals of Oncology (2016)
Regenerative nodular hyperplasia (RNH) induced by oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM): A contraindication for major liver resection?
Authors: B. Aussilhou, E. Ragot, S. Dokmak, S. J. Faivre, V. Paradis, J. Belghiti
Journal: Journal of Clinical Oncology (2011)

179 Background: Oxaliplatin is recognized to induce vascular lesions in the nontumoral liver parenchyma. Regenerative nodular hyperplasia (RNH), the ultimate state of the vascular lesions, is very rare. In some reported cases, RNH was associated with severe lethal postoperative complications after hepatic resection. This study aimed to compare the postoperative course after major hepatectomy, in patients with colorectal liver metastases treated with oxaliplatin-based chemotherapy, with or without RNH in the resected specimen. Methods: Between 2001 and 2009, among 420 patients who underwent liver resection for CRLM, 17 (4%) patients had RNH lesions (RNH+ group) on the resected specimen after right hepatectomy. These 17 patients were compared to another group of 20 patients with similar clinicopathologic data but without RNH (RNH- group) who underwent right hepatectomy. The mean age of the RNH + and RNH- groups was 57 years (range: 37-71 years) and 60 years (range: 43-73 years), respectively. Preoperatively the patients were treated with a mean number of 7 cycles of oxaliplatin (range: 3-12 cycles). The peroperative blood loss (560 vs. 830 ml) and blood transfusion (18% vs. 20%) were similar in the two groups. Results: The mortality in the RNH+ group and the RNH- group (6% vs. 5%, respectively) were similar (p&gt;0.005). The postoperative morbidity was 53% in the RNH+ group and 35% in RNH– group (p&gt;0.005). The most frequent complications were biliary fistula (3 in the RNH+ group and 2 in the RNH- group) and pulmonary complications (6 in the RNH+ group and 5 in the RNH- group). However, the post operative ascites was significantly encountered in the RNH+ group with 70% of patients compared with 40% in the RNH- group. The number of patients who had a bilirubin level at day 5 superior to 50 was significantly higher in the RNH+ group (35%) compared with 15% in the RNH-group. Conclusions: RNH lesions allow major hepatectomy without increased mortality but with increased postoperative ascites and jaundice justifying preoperative liver biopsy to detect this lesion with subsequent portal embolisation or sparing liver resection in order to avoid major resections. No significant financial relationships to disclose.
FIRSTANA: Health-related quality of life (HRQL) and post-hoc analyses for the phase III study assessing cabazitaxel (C) vs docetaxel (D) in chemotherapy-naïve patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Authors: S. Oudard, O. Sartor, L. Sengeløv, G. Daugaard, F. Saad, S. Hansen, M. Hjelm-Eriksson, J. Jassem, A. Thiery-Vuillemin, O. Caffo, D. Castellano, P.N. Mainwaring, J. Bernard, L. Shen, M. Chadjaa, K. Fizazi
Journal: Annals of Oncology (2016)
biomarkers Exploratory biomarkers in MONARCH 1, a phase II study of abemaciclib monotherapy in hormone-receptor positive (HR ) HER2- metastatic breast cancer (MBC)
Authors: S.M. Tolaney, J. Cortes, M.N. Dickler, E. Zamora, C.W. Caldwell, T.S. Nguyen, S. Nanda, A. Koustenis, H.S. Rugo
Journal: Annals of Oncology (2016)
Noninvasive pressure ventilation in patients with acuteexacerbation of chronic obstructive pulmonary disease withacute respiratory failure
Authors: Pavel Matuška, Olga Pilařová, Jana Skřičková
Journal: European Respiratory Journal (2005)

On a group of patients with acute exacerbation of chronic
obstructive lung disease and respiratory failure, the authors
study the influence of noinvasive pulmonary ventilation.
Three-year estimate of overall survival in COMBI-v, a randomized phase 3 study evaluating first-line dabrafenib (D) + trametinib (T) in patients (pts) with unresectable or metastatic BRAF V600E/K–mutant cutaneous melanoma
Authors: C. Robert, B. Karaszewska, J. Schachter, P. Rutkowski, A. Mackiewicz, D. Stroyakovskiy, R. Dummer, F. Grange, L. Mortier, V. Chiarion-Sileni, K. Drucis, I. Krajsová, A. Hauschild, B. Mookerjee, J.J. Legos, Y. Zhang, S. Lane, D. Schadendorf
Journal: Annals of Oncology (2016)
Extended adjuvant temozolamide as prognostic factor of longer overall and progression-free survival in glioblastoma multiforme
Authors: S.C. Póvoa, N. Tavares, M.J. Ribeiro, D. Azevedo, A. Coelho, A. Fernandes, A. Costa, C. Caeiro, B. Carvalho, P. Linhares, L. Osório, L. Castro, J. Fonseca, M. Damasceno
Journal: Annals of Oncology (2016)
Phase III clinical trials in chemotherapy-naive patients with advanced NSCLC assessing the combination of atezolizumab and chemotherapy
Authors: M. Reck, V.A. Papadimitrakopoulou, F. Cappuzzo, R. Jotte, T.S.K. Mok, A. Sandler, D. Waterkamp, S. Coleman, T. Asakawa, M. Socinski
Journal: Annals of Oncology (2016)
MNGO-02. A META-ANALYSIS OF PUBLISHED LITERATURE ON ADJUVANT RADIOSURGERY AND SURVEILLANCE FOLLOWING SUBTOTAL RESECTION OF ATYPICAL MENINGIOMA
Authors: Carlito Lagman, Nikhilesh Bhatt, Panayiotis Pelargos, Seung Lee, Debraj Mukherjee, Isaac Yang
Journal: Neuro-Oncology (2016)

The role of adjuvant radiosurgery (ARS) in the management of atypical meningioma (AM) has yet to be defined, but recent studies suggest improved outcomes in a subset of patients with minimal residual or recurrent tumor volume following surgical resection. The authors of this paper performed a meta-analysis of the available published literature and collated data to compare outcomes of patients with AM treated with ARS and those undergoing surveillance following subtotal resection (STR). Embase, PubMed, and Cochrane databases were queried using search terms ‘atypical meningioma’ AND ‘adjuvant’ with a combined 13 articles deemed eligible for data extraction after rigorous screening. A subsequent search using terms ‘atypical meningioma’ AND ‘subtotal’ ultimately resulted in 11 articles deemed eligible for data extraction. Adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were maintained throughout this study. A total of 335 patients with AM treated with radiosurgery were identified. Median recurrence rate (RR), progression-free survival (PFS) and overall survival (OS) at 5-years of those reported were 38%, 66.5% and 77%, respectively. A total of 359 patients with AM undergoing subtotal resection without post-operative radiation were identified. Median RR, PFS and OS of those reported were 62.7%, 90% and 93.1%, respectively. ARS is associated with fewer recurrences, increased PFS, but decreased OS, when compared to surveillance following STR. Given the inherent limitations of retrospective reviews and the inconsistencies of data reporting and analysis, we remain cognizant of the inevitable imprecision of our results. Future retrospective studies should collect uniform outcome measures in larger cohorts. Randomized-controlled trials (RCT) comparing ARS and surveillance following STR are critical in establishing a role, or lack thereof, for adjuvant radiosurgery following subtotal resection of atypical meningioma.
A phase I trial of romidepsin in combination with gemcitabine in patients with pancreatic and other advanced solid tumors
Authors: H. H. Doss, S. F. Jones, J. R. Infante, D. R. Spigel, N. Willcutt, R. Lamar, J. Barton, M. Keegan, H. A. Burris
Journal: Journal of Clinical Oncology (2008)

2567 Background: Romidepsin is a histone deacetylase (HDAC) inhibitor that inhibits ras-mediated and MAP kinase signal transduction causing cell cycle arrest. Preclinical studies of romidepsin and gemcitabine in xenografts of ras transformed pancreatic cancer demonstrated significant antitumor activity for the combination compared to gemcitabine alone. Long-term effects were observed on tumor cell growth and cell cycle regulators following treatment cessation, suggesting down regulation of HDAC activity. This trial evaluated the safety and tolerability of romidepsin in combination with gemcitabine. Methods: Premedications consisted of a serotonin antagonist plus dexamethasone. Romidepsin was administered as a 4 hour infusion followed by gemcitabine over 30 minutes on days 1, 8, and 15 of a 28 day cycle. Results: Thirty-three patients (9 pancreatic, 8 breast, 7 NSCLC, 3 ovarian, 6 other; 23 F/10M) have received 104+ cycles (median 2, range 1 - 8). The initial romidepsin/gemcitabine dose level was 10/800 mg/m2, but 4/7 patients required dose omissions on days 8 or 15 due to thrombocytopenia (<75,000) or neutropenia (≤ 1,000) and were considered to have dose-limiting toxicity (DLT). Subsequently, the romidepsin was decreased to 7 mg/m2. At this dose level, 6/7 patients missed doses due to DLTs of thrombocytopenia and/or neutropenia. As a result, the day 8 dose was eliminated. Three dose levels have been explored on the every other week schedule. Ten patients were enrolled at 10/800 mg/m2 and 2/10 experienced a DLT (grade 4 thrombocytopenia, ↑LFTs). Six patients were enrolled at 10/1,000 mg/m2 with 2/6 experiencing dose-limiting grade 4 thrombocytopenia. Concurrently, the romidepsin was increased to 12 mg/m2 in combination with gemcitabine 800 mg/m2 and no DLTs were reported in 3 patients. Nonhematologic toxicities have been mild to moderate and consist primarily of nausea, vomiting, and fatigue. One patient with ovarian cancer experienced a minor response (29% ↓) and 12 pts experienced stable disease for ≥ 4 cycles (5 pancreatic, 4 breast, 1 NHL, 1 ovarian, 1 ampullary cancer). Conclusions: The recommended phase II dose (romidepsin 12 mg/m2 and gemcitabine 800 mg/m2 every other week) is being expanded to further assess the safety and activity of the regimen. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Gloucester Pharmaceuticals Gloucester Pharmaceuticals
ZUMA-2: A phase 2 multi-center study evaluating the efficacy of KTE-C19 (Anti-CD19 CAR T cells) in patients with relapsed/refractory Mantle cell lymphoma (R/R MCL)
Authors: M. Wang, F.L. Locke, T. Siddiqi, J. Castro, B. Shah, H. Lee, L.E. Budde, M. Choi, C. Anasetti, R. Champlin, S. Forman, T. Kipps, A. Bot, J.M. Rossi, L. Navale, Y. Jiang, J. Aycock, M. Elias, J. Wiezorek, W.Y. Go
Journal: Annals of Oncology (2016)
Next Gen Dissection of Gfi1 Dependent Transcriptome in Myeloid Progenitors Reveals Global Control of Multiple Transcriptional Programs Including Coding and Non Coding RNAs
Authors: H. Andre Olsson, Andrew Plassard, Phillip Dexheimer, Berthold Göttgens, Ari Melnick, Bruce J Aronow, H. Leighton Grimes
Journal: Blood (2012)
Hematopoietic Cell Kinase (HCK) Is Highly Expressed in Myelodysplastic Syndrome (MDS) and Regulates Proliferation, Cell Cycle Progression and Hematopoietic Differentiation
Authors: Fernanda Marconi Roversi, João Machado-Neto, Bruna Palodetto, Flávia Adolfo Corrocher, Mariana Ozello Baratti, Paula de Melo Campos, Fabiola Traina, Sara T Olalla Saad
Journal: Blood (2012)
Prophylaxis of chemotherapy-induced neutropenia with lipegfilgrastim in patients with breast cancer: results from an interim analysis of the non-interventional study NADIR
Authors: C.M. Kurbacher, T. Fietz, T. Trarbach, C. Salat, M. Rezai, A. Lorenz, B. Niemeier
Journal: Annals of Oncology (2016)
Patients over Age 40 with Ph-Negative Acute Lymphoblastic Leukemia Do Not Benefit from Allogeneic Transplant in First Remission. Retrospective Analysis from a Large Tertiary Center
Authors: Ofir Wolach, Kristen Stevenson, Martha Wadleigh, Daniel J. DeAngelo, David P. Steensma, Robert J. Soiffer, Joseph H Antin, Donna S Neuberg, Vincent T. Ho, Richard M. Stone
Journal: Blood (2015)
DDIS-10. TARGETING HGF/MET IN GBM BY RESTORING SPINT2 FUNCTION
Authors: Fei Liu, Zhenfu Han, Partha Karmakar, Tie Li, James W Janetka, Albert Lai
Journal: Neuro-Oncology (2016)

Glioblastoma (GBM) represents the most lethal form of primary glioma and not incurable with currently available surgical, radiation and chemotherapeutic modalities. Intensive molecular characterization of GBM has revealed a rich inter-tumoral diversity of molecular aberrations indicating the promise of personalized targeted therapies. In our previous study, we identified SPINT2 (Serine Protease Inhibitor, Kunitz Type, 2) from an unbiased promoter hypermethylation screen as one of the top cancer-related genes epigenetically downregulated by CpG island methylation in GBM. SPINT2 encodes a transmembrane glycoprotein that physiologically inhibits a broad spectrum of serine proteases including HGF activator (HGFA) and matriptase. Both HGFA and matriptase, often upregulated in a variety of tumors, are major physiological proteases proteolytically activating HGF/MET signaling. Analysis of TCGA indicates that matriptase is ubiquitously overexpressed in GBM in addition to SPINT2 down-regulation. Thus, the imbalanced activity of these serine proteases is presumably to enhance MET activation in the GBM exhibiting MET and HGF co-expression. Building on our prior data showing that SPINT2 re-expression restricted the growth and migration of glioma cells via down-regulating MET signaling, in vitro treatment with commercially available recombinant SPINT2 strongly suppressed MET signaling as well as glioma cell migration. We also show that SPINT2 re-expression suppressed glioma tumor growth in vivo and prolonged the survival of mice bearing intracranial tumors. Using a series of selective rationally designed serine protease inhibitors of HGFA, matriptase and hepsin, we found that these inhibitors could mimic SPINT2 activity by suppressing MET activation resulting in decreased tumor cell proliferation and anchorage-independent growth. In summary, we provide evidence that targeting imbalanced activity of HGF-activating serine proteases potentially serves as an innovative MET-targeting therapeutic strategy for GBM.
BMET-27. PROGNOSTIC FACTORS IN TREATMENT OF CEREBRAL METASTASES
Authors: Daniel Pinggera, Johannes Kerschbaumer
Journal: Neuro-Oncology (2016)

Regardless of treatment advances, the prognosis of brain metastasis is dismal. Adequate drug delivery is counteracted by the blood-brain barrier. Surgical resection followed by radiotherapy (or SRS) remains the main option for these patients. We investigated radiological and clinical data to identify factors influencing overall survival (OS) in patients with cerebral metastases. Special emphasis was put on the extent of edema, which has been discussed as a marker of infiltration and thus aggressiveness of the tumor. 143 patients with cerebral metastasis (m:f=1,1:1) who underwent surgical resection were retrospectively analyzed. The volume of tumor (Vmet) and edema (Ved) was calculated using Osirix. To facilitate statistical analysis, the cohort was dichotomized according to a coefficient calculated from the volumetric data of metastasis and edema (Ved / Vmet). Statistical analysis was performed to assess the influence of tumor and edema volume in addition to other clinical parameters on OS. The median Vmet amounted to 15,2cc (0,8-90,8) and the median Ved to 40,4cc (0-179,9). Divided in the different primaries, a significant correlation of the tumor volume to OS could be shown in lower GIT (p=0,02), melanoma (p=0,01) and lung cancer (p<0,001). 41 patients (28,6%) showed small edema (coefficient <1) and 102 patients (71,4%) presented with large edema (coefficient >1). Metastases within the cerebellum had significantly less edema (p<0,001). The factors associated with prolonged OS were extent of resection (biopsy/GTR p=0,001; biopsy/STR p=0,04; STR/GTR n.s.), WBRT (p<0,001), female sex (p=0,029), RPA-class (RPA1/RPA2/RPA3 p=0,005, OR 2,212). There was no correlation between OS and the coefficient Ved / Vmet (p=0,381, OR=1,188(0,812-1,739)). The outcome of cerebral metastases was influenced by extent of resection, postoperative radiotherapy and RPA-class. Nevertheless, in some subgroups of our cohort, there was a significant relationship between tumor volume and OS. A relationship of Ved with OS could not be detected.
Autophagic Cell Death in Leukemia Cells Regulated by Ceramide and Sphingosine-1-Phosphate through Mammalian Target of Rapamycin.
Authors: Nari Harakawa, Ken Murata, Shohei Yamaoka, Toshiaki Hori, Naochika Domae, Yasuyuki Igarashi, Hisanori Umehara, Toshiro Okazaki
Journal: Blood (2005)
Anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 immunotherapy for prostate cancer
Authors: S.T. Tagawa, D. Scherr, J. Batra, Y. Jhanwar, B. Robinson, D. Nanus, H. Beltran, A. Molina, P. Christos, N. Bander
Journal: Annals of Oncology (2016)
Internal and External Determinants of Bleeding Patterns on Prophylaxis for Severe Haemophilia A.
Authors: Kathelijn Fischer, Peter Collins, Jan Astermark, Victor S. Blanchette, Sven Bjorkman, Myungshin Oh, Phillip Schroth, Sandor Fritsch, Kathleen M. Casey, Gerald Spotts, Bruce M. Ewenstein
Journal: Blood (2007)