tbuckley/cabot-search huggingface dataset:
Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations
Authors: Uzay E. Emir, Sarah J. Larkin, Nick de Pennington, Natalie Voets, Puneet Plaha, Richard Stacey, Khalid Al-Qahtani, James Mccullagh, Christopher J. Schofield, Stuart Clare, Peter Jezzard, Tom Cadoux-Hudson, Olaf Ansorge
Journal: Cancer Research (2015)

Abstract Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy (1H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo 1H-MRS spectra discriminated between IDH-mutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy. Cancer Res; 76(1); 43–49. ©2015 AACR.
Activation of ER-α by DNMT and HDAC inhibitors radiosensitizes ER-α negative breast cancer cells
Authors: Anupama Munshi, Thomas Buchholz, Khandan Keyomarsi, Raymond Meyn
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

3104 

Loss of estrogen receptor-α (ER-α) expression in breast cancers is associated with increased tumor grade and proliferation. Moreover, ER negative tumors have been shown to be less responsive to radiotherapy in clinical trials. Increasing evidence suggests that epigenetic alterations play a role in the inactivation of ER gene expression. DNA hypermethylation of CpG islands located within the promoters of ERa is one mechanism for the loss of ER gene transcription in ER-negative tumors and some human breast cancer cell lines. The demethylating agent, 5-aza-2’-deoxycytidine (5-Aza-dC), can restore gene expression leading to re-expression of functional ER protein. Methylated DNA can also serve as a substrate to recruit Histone Deacetylase (HDAC) activity leading to silencing of genes through local deacetylation of histone proteins. We hypothesized that ER-negative human breast cancers are radioresistant due to hypermethylation and hypoacetylation of the ER gene and that restoration of ER expression in ER-negative cells by treatment with the demethylating agent (5-Aza-dC) and HDAC inhibitors would restore sensitivity to radiation therapy. We used two human ER-negative breast cancer cell lines (MDA-MB-231 and Hs578t) and one ER-positive cell line (MCF-7 cells, positive control) to test the effect of these inhibitors. In addition, MDA-MB-231 cells transfected with either control vector or wild-type human ER-a were used as appropriate controls. To investigate the ability of these agents in modulating cellular responses to ionizing radiation, cells were pretreated with the HDAC inhibitor for 24 hr or Zebularine (a relatively non toxic analog of 5-Aza-dC) for 24, 48 and 72hr, followed by radiation at doses of 2, 4 and 6 Gy. Clonogenic cell survival assays were performed and our preliminary data demonstrates that both the drugs can independently restore radiosensitivity to MDA-MB-231 cells. Similar results were obtained with MB-231 cells stably overexpressing ER-α. These cells were found to be relatively more radiosensitive when compared with the cells transfected with the control vector. Both these agents were able to reactivate ER-α leading to expression of detectable protein in MDA-MB-231 and Hs578t cells. The ability of the re-expressed ER protein to mediate an estrogen response is currently being tested using a plasmid containing a luciferase gene under the transcriptional regulation of estrogen responsive element (ERE) driving a thymidine kinase promoter stably transfected into MDA-MB-231 and Hs578t cells. We are also investigating the ability of the drug-induced ER to activate expression of endogenous ER-responsive genes such as progesterone receptor (PR). Though preliminary, our data suggests that a combination of both DNA methyl transferase inhibitors and HDAC inhibitors can activate ER protein which in turn makes the cells responsive to ionizing radiation.
T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes
Authors: Daniele Mennonna, Cristina Maccalli, Michele C Romano, Claudio Garavaglia, Filippo Capocefalo, Roberta Bordoni, Marco Severgnini, Gianluca De Bellis, John Sidney, Alessandro Sette, Alessandro Gori, Renato Longhi, Marco Braga, Luca Ghirardelli, Ludovica Baldari, Elena Orsenigo, Luca Albarello, Elisabetta Zino, Katharina Fleischhauer, Gina Mazzola, Norma Ferrero, Antonio Amoroso, Giulia Casorati, Giorgio Parmiani, Paolo Dellabona
Journal: Gut (2015)

Objective Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies. Design We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions. Results Several unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8 + and CD4 + T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8 + T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo. Conclusions These results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.
GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy (RT) followed by either consolidation (C) with NVBo plus P plus best supportive care (BSC) or BSC alone in stage (st) III non-small cell lung cancer (NSCLC): Final results of a phase (ph) III study.
Authors: Rudolf M. Huber, Walburga Engel-Riedel, Jens Kollmeier, Stefan Andreas, Susanne Staar, Gunther Klautke, Rainer Fietkau, Nathalie Vaissiere, Susanne Osowski, Michael Flentje
Journal: Journal of Clinical Oncology (2012)

7001 Background: Concurrent chemo-radiotherapy (CT-RT) is considered as a standard in st III NSCLC. Published trials with C after CT-RT show encouraging but discordant results. This ph III was set up to assess C in st III NSCLC. Methods: Patients (pts) received NVBo 50 mg/m² D1, D8, D15 + P 20 mg/m² D1-D4 q4w / 2 cycles (cy) + RT (66 Gy / 33 Fr). C for OR+SD pts: NVBo 60-80 mg/m² D1D8 + P 80 mg/m² D1 q3w / 2 cy + BSC (Arm A) or BSC (Arm B). PFS was the primary endpoint. Results: From 07/05 to 05/09, 279 pts received CT/RT and 201 pts (72%) were randomised to receive CT+BSC or BSC as C. Toxicity (tox) G3-4 (% pt) CT-RT/ C (Arm A/B): anaemia 3.2/3.5/1.1; thrombopenia 2.5/1.2/0.6; neutropenia (N) 11.2/11.7/5.7; febrile N 1.4/1.0/0; nausea (G3) 5.0/4.7/2.9; vomiting (G3) 3.9/3.5/2.0; anorexia 3.6/1.2/3.0; dysphagia 1.8/2.3/1.0; fatigue 3.3/ 2.3/1.0; pneumonia/ pneumonitis 2.6/0/2.0; CT-RT pain 2.2; CT-RT oesophagitis 8.6; 3 toxic deaths. Conclusions: In this ph III, NVBo+P+RT reports a high level of efficacy (OR 60.7%; DCR 86.0%) and low tox. The DCR is significantly improved in pts who received C with NVBo+ P in eval pts (p=0.0084). Lung tox was not enhanced by using NVBo+P as C. However no survival advantage for C was achieved. [Table: see text]
Invasive Bladder Cancer: Genomic Insights and Therapeutic Promise
Authors: Jaegil Kim, Rehan Akbani, Chad J. Creighton, Seth P. Lerner, John N. Weinstein, Gad Getz, David J. Kwiatkowski
Journal: Clinical Cancer Research (2015)

Abstract Invasive bladder cancer, for which there have been few therapeutic advances in the past 20 years, is a significant medical problem associated with metastatic disease and frequent mortality. Although previous studies had identified many genetic alterations in invasive bladder cancer, recent genome-wide studies have provided a more comprehensive view. Here, we review those recent findings and suggest therapeutic strategies. Bladder cancer has a high mutation rate, exceeded only by lung cancer and melanoma. About 65% of all mutations are due to APOBEC-mediated mutagenesis. There is a high frequency of mutations and/or genomic amplification or deletion events that affect many of the canonical signaling pathways involved in cancer development: cell cycle, receptor tyrosine kinase, RAS, and PI-3-kinase/mTOR. In addition, mutations in chromatin-modifying genes are unusually frequent in comparison with other cancers, and mutation or amplification of transcription factors is also common. Expression clustering analyses organize bladder cancers into four principal groups, which can be characterized as luminal, immune undifferentiated, luminal immune, and basal. The four groups show markedly different expression patterns for urothelial differentiation (keratins and uroplakins) and immunity genes (CD274 and CTLA4), among others. These observations suggest numerous therapeutic opportunities, including kinase inhibitors and antibody therapies for genes in the canonical signaling pathways, histone deacetylase inhibitors and novel molecules for chromatin gene mutations, and immune therapies, which should be targeted to specific patients based on genomic profiling of their cancers. Clin Cancer Res; 21(20); 4514–24. ©2015 AACR.
Prognostic (Px) significance of Ki67 before and after neoadjuvant chemotherapy (CT) in early breast cancer
Authors: R. L. Jones, J. Salter, A. Nerurkar, M. Parton, R. A’Hern, I. E. Smith, M. Dowsett
Journal: Journal of Clinical Oncology (2007)

573 Background: High levels of the proliferation marker Ki67 are associated with a higher response rate to CT but poorer long-term outcome. The Px significance of Ki67 before CT and at surgical excision was compared. Methods: 103 patients treated with CT with pre- and post- (excision) CT tissue and a further 181 with only excision tissue available were identified, 37 and 76 of these respectively were ER+ and also received tamoxifen. The following factors were considered pre-CT and at excision (where relevant) for their relationship with relapse-free (RFS) and overall (OS) survival: ER, PR, HER2, grade, Ki67, histological type, vascular invasion, age/menses, T and N stage, pre-therapy operability, clinical response, CT regimen, type of surgery, adjuvant therapy, pathological tumour size and nodal involvement. Results: In the paired cohort univariate analysis of RFS the following factors were associated with poorer Px (a) pre-CT: ER- (p=0.003); increasing T stage (p&lt;0.001), N stage (p=0.002) and Ki67 (p&lt;0.001); (b) at excision: increasing grade (p=0.01), tumour size (p=0.02), nodal status (p&lt;0.001) and Ki67 (p&lt;0.001); no adjuvant endocrine therapy (p&lt;0.001). On multivariate analysis only excision Ki67 (p&lt;0.001) was significant although there was a suggestion pre-therapy Ki67 was important (p&lt;0.10). On univariate analysis of OS the following factors associated with poorer Px (a) pre-CT: ER- (p=0.006); increasing T stage (p&lt;0.001) and Ki67 (p&lt;0.001); (b) at excision: increasing grade (p=0.04), tumour size (p=0.005), nodal status (p&lt;0.03) and Ki67 (p&lt;0.001); no adjuvant endocrine therapy (p=0.001). On multivariate analysis both pre-CT and excision Ki67 were significant independent predictors but the latter was more highly significant. (p&lt;0.02 + p&lt;0.0001, respectively) Assessing the combined group of 284 patients, after 5 years the highest and lowest tertiles of excision Ki67 had strikingly different Px: RFS 36% and 73%; OS 50% and 85%, respectively. Conclusions: Ki67 after CT is a strong predictor of long-term outcome. The greater significance of Ki67 in the excision sample may be due to this identifying patients in whom residual highly proliferative disease remains after CT. No significant financial relationships to disclose.
A phase III randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinb in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19.
Authors: G. D. Goss, I. Lorimer, M. S. Tsao, C. J. O'Callaghan, K. Ding, G. A. Masters, P. Roberts, J. R. Jett, M. J. Edelman, F. A. Shepherd
Journal: Journal of Clinical Oncology (2010)

LBA7005 Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC. Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug. Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size &gt;4cm was predictive of poor DFS (p&lt;0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib. Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented. [Table: see text]
The effects of paclitaxel (PTX) and 2-methoxyestradiol (2-ME<sub>2</sub>) on tumor oxygenation and HIF-1α in breast cancer
Authors: K. L. Blackwell, J. Chi, C. Sidor, P. Burke, T. LaVallee, H. S. Shaw, V. Liotcheva, D. Sims, L. Hobbs, J. Arnott, M. W. Dewhirst
Journal: Journal of Clinical Oncology (2007)

3517 Background: Radiation activates HIF-1a via a free radical mediated mechanism associated with reoxygenation. This response could be inhibited, resulting in reduced tumor vascularity and proliferation. Preclinical breast cancer models and a Phase Ib clinical trial (CT) were employed to look at the effects of chemo with or without an oral HIF-1a inhibitor, 2-ME 2 (EntreMed) on tumor oxygenation and HIF-1a. Methods: Preclinical models of chemo effects on HIF-1a/oxygenation used 4T1 tumors and either doxorubicin (DOX) or cyclophosphamide (CTX). In addition, MDA-MB-231 tumors were treated with 2-ME2 (5days), and HIF-1a/MVD was assessed. In the CT, up to 15 pts with metastatic breast cancer, and biopsiable (&gt;2 cm) non-bone sites were eligible. Tx was: D 1: PTX, 90 mg/m 2 ; D 8: PTX, 90 mg/m 2 with 2-ME 2 (cohorts of 1,000/1,250/1,500 mg, qid). PTX was given 3 out of 4 wks. Bxs were done at enrollment, D8 (post-PTX), and D22 (post-PTX/2-ME 2 ). Tumors were examined for changes in HIF-1a and CA9 levels, MVD, and genomic signatures of hypoxia. Plasma was obtained for osteoponin, PAI-1, and VEGF. Results: DOX and CTX both led to increases in HIF-1a, oxygenation, vascularity, and proliferation 4–10 days post treatment in the 4T1 model, while 2-ME2 reduced HIF-1a and MVD post treatment (5 d) in the MDA-MB-231 model. The CT opened in 6–2006, 9 pts have consented and 8 pts have undergone sequential biopsies and accrual continues. No DLT have been seen. Biopsy sites include chest wall, liver, and LN. Sufficient tissue/RNA/plasma has been obtained and the planned analyses will be presented. Conclusions: HIF-1a and tumor oxygenation appear to be modulated as a response to chemotherapy. The combination of PTX and 2-ME 2 is clinically active, well-tolerated, and could serve as one of the first approaches to target HIF-1a in order to optimize therapy. Supported by Komen Grant BCTR0504044. [Table: see text]
Cytokines in Metastatic Renal Cell Carcinoma: Is It Useful to Switch to Interleukin-2 or Interferon After Failure of a First Treatment?
Authors: Bernard Escudier, Christine Chevreau, Christine Lasset, Jean Yves Douillard, Alain Ravaud, Michel Fabbro, Armelle Caty, Jean Francois Rossi, Patrice Viens, Jean Pierre Bergerat, Jacqueline Savary, Sylvie Négrier
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFNα2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFNα2a as second-line treatment after failure of the other cytokine. PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFNα2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 × 10 6 IU/m 2 /d), and IFNα2a was administered three times weekly at 18 × 10 6 IU. RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFNα2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFNα2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFNα2a. CONCLUSION: Cross-over after failure of IL-2 or IFNα2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.
Monoclonal anti‐envelope antibody AP33 protects humanized mice against a patient‐derived hepatitis C virus challenge
Authors: Isabelle Desombere, Samira Fafi‐Kremer, Freya Van Houtte, Patrick Pessaux, Ali Farhoudi, Laura Heydmann, Lieven Verhoye, Sarah Cole, Jane A. McKeating, Geert Leroux‐Roels, Thomas F. Baumert, Arvind H. Patel, Philip Meuleman
Journal: Hepatology (2015)

End‐stage liver disease (ESLD) caused by hepatitis C virus (HCV) infection is a major indication for liver transplantation. However, immediately after transplantation, the liver graft of viremic patients universally becomes infected by circulating virus, resulting in accelerated liver disease progression. Currently available direct‐acting antiviral therapies have reduced efficacy in patients with ESLD and prophylactic strategies to prevent HCV recurrence are still highly needed. In this study, we compared the ability of two broadly reactive monoclonal antibodies (mAbs), designated 3/11 and AP33, recognizing a distinct, but overlapping, epitope in the viral E2 glycoprotein to protect humanized mice from a patient‐derived HCV challenge. Their neutralizing activity was assessed using the HCV pseudoparticles and cell‐culture–derived HCV systems expressing multiple patient‐derived envelopes and a human‐liver chimeric mouse model. HCV RNA was readily detected in all control mice challenged with a patient‐derived HCV genotype 1b isolate, whereas 3 of 4 AP33‐treated mice were completely protected. In contrast, only one of four 3/11‐treated mice remained HCV‐RNA negative throughout the observation period, whereas the other 3 had a viral load that was indistinguishable from that in the control group. The increased in vivo efficacy of AP33 was in line with its higher affinity and neutralizing capacity observed in vitro . Conclusions: Although mAbs AP33 and 3/11 target the same region in E2, only mAb AP33 can efficiently protect from challenge with a heterologous HCV population in vivo . Given that mAb AP33 efficiently neutralizes viral variants that escaped the humoral immune response and reinfected the liver graft of transplant patients, it may be a valuable candidate to prevent HCV recurrence. In addition, our data are valuable for the design of a prophylactic vaccine. (H epatology 2016;63:1120–1134)
Association Between Child Poverty and Academic Achievement
Authors: Alma L. Golden
Journal: JAMA Pediatrics (2015)

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