tbuckley/cabot-search huggingface dataset:
NIMG-67. CLINICAL APPLICATIONS OF QUANTITATIVE THREE-DIMENSIONAL MRI ANALYSIS FOR PEDIATRIC EMBRYONAL BRAIN TUMORS
Authors: Jared Hara, Ashley Wu, Javier Villanueva-Meyer, Gilmer Valdes, Vikas Daggubati, Sabine Mueller, Timothy Solberg, Steve Braunstein, Olivier Morin, David Raleigh
Journal: Neuro-Oncology (2018)

OBJECTIVES: Pediatric embryonal brain tumors include medulloblastoma, supratentorial primitive neuroectodermal tumor, and pineoblastoma. The purpose of this study was to investigate the prognostic utility of quantitative three-dimensional (3D) magnetic resonance imaging (MRI) radiomic analysis for primary pediatric embryonal brain tumors. Thirty-four pediatric embryonal brain tumor patients with concurrent pre-operative T1-weighted post contrast (T1PG) and T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images were identified from an institutional database. The median imaging follow-up was 5.2 years. Radiomic features were extracted from axial T1PG and FLAIR contours using MATLAB, and 15 features were selected for analysis based on qualitative radiographic features with known prognostic significance for pediatric embryonal brain tumors. Logistic regression, linear regression, receiver operating characteristic curve, Harrells C index and Somers D index were used to test the relationships between radiomic features, demographic variables and clinical outcomes. We found that pediatric embryonal brain tumors in older patients had increased normalized mean tumor intensity (P=0.05, T1PG), decreased tumor volume (P=0.02, T1PG) and increased markers of heterogeneity (P0.01, T1PG and FLAIR) relative to younger patients. We identified 10 quantitative radiomic features that delineated between medulloblastoma, pineoblastoma and supratentorial primitive neuroectodermal tumor, including size and heterogeneity (P0.05, T1PG and FLAIR). Decreased markers of tumor heterogeneity were predictive of neuraxis metastases and trended towards significance (P=0.1, FLAIR). Tumors with increased size (AUC=0.7, FLAIR) and decreased heterogeneity (AUC=0.7, FLAIR) at diagnosis were more likely to recur. CONCLUSIONS: Quantitative radiomic features are associated with pediatric embryonal brain tumor patient age, histology, neuraxis metastases and recurrence, and could be used for risk stratification.
CBMT-10. GLUTAMINE DEPRIVATION ALTERS ONE-CARBON METABOLISM TO MAINTAIN GLIOMA CELL SURVIVAL
Authors: Kazuhiro Tanaka, Takashi Sasayama, Takiko Uno, Masahiro Maeyama, Yuichi Fujita, Yasuhiro Irino, Eiji Kohmura
Journal: Neuro-Oncology (2018)

Cancer cells acquire and utilize necessary nutrients to survive from a frequently poorly nutrient environment. This metabolic processes include cellular biosynthesis, redox maintenance and epigenetic regulation through nucleic acid and protein methylation, leading to selection for cancer cells with increasing tumorigenicity and therapy-resistance. But less is known about how cancer cells alter metabolism to support cell growth and survival from nutrient starvation. Here, we identify that one-carbon metabolism integrated cellular nutrient status by cycling carbon units from amino acids to support cell proliferation. To identify metabolic response to glutamine deprivation in glioma cells, we analyzed metabolites using gas chromatography and mass spectroscopy (GC/MS) in glioma cells cultured in glutamine-deprived medium and examined gene expression of key enzymes for one-carbon units using RT-PCR and western blotting methods. These expressions were also confirmed by immunohistochemical staining in glioma clinical samples. Metabolome studies indicated serine, cysteine, and methionine as key differentiating amino acids between control and glutamine-deprived groups. Gene expression analysis identified upregulation of Phosphoserine aminotransferase 1 (PSAT1)Serine hydroxymethyl transferase 2 (SHMT2), and Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to regulate serine synthesis and one-carbon metabolism. Importantly, suppression of these metabolites impaired glioma cells in glutamine-deprived condition. In human glioma samples. SHMT2 and MTHFD2 expressions were highest in poorly nutrient regions around “pseudopalisading necrosis”. One-carbon metabolism has a key role for glioma cells to survive glutamine deprivation. These results may suggest the new therapeutic strategies targeting critical glioma cells adapting the tumor microenvironment.
Abstract 12336: Effect of Coffee With a High Content of Chlorogenic Acids and Low Content of Hydroxyhydroquinone on Postprandial Endothelial Dysfunction
Authors: Masato Kajikawa, Tatsuya Maruhashi, Takayuki Hidaka, Yukiko Nakano, Satoshi Kurisu, Takeshi Matsumoto, Yumiko Iwamoto, Shinji Kishimoto, Shogo Matsui, Haruki Hashimoto, Farina B Yusoff, Yasuki Kihara, Kensuke Noma, Ayumu Nakashima, Takuya Watanabe, Hiroshi Tone, Masanobu Hibi, Noriko Osaki, Yoshihisa Katsuragi, Yukihito Higashi
Journal: Circulation (2017)

Introduction: Coffee contains an abundance of polyphenols. However, the association between coffee drinking and risk of cardiovascular disease is controversial. Roasting coffee results in loss of t...
EXTH-42. CANSCRIPT MAY PREDICT A SUBSET OF GLIOBLASTOMAS THAT RESPOND TO SP1 BLOCKERS
Authors: Amitava Ray, Sarvanan Thiyagarajan, Biswanath Majumdar, Padhma Radhakrishnan, Ajith Kamath, Dilli Kumar, Pradip Majumdar
Journal: Neuro-Oncology (2018)

Perturbation of SP1 has long been implicated in the pathogenesis and drug resistance in Glioblastomas. Multiple mechanisms including upregulation of BACH 1 by antagonizing the function of P53 and hypomethylating MGMT have been described. In addition, the increased expression of genes involved in promoting cancer stem cells may orchestrate this resistance. Biopsied GBM samples (n=25) were evaluated for response to SP1 inhibitor using CANscript, a clinically relevant ex vivo platform. CANscript system incorporates a personalized tumor microenvironment approach for treatment evaluation and yields a high degree of predictive correlation to patient clinical outcomes (Majumder B et al. Nature Communications, 2015). Out of the 25 samples evaluated 10 samples were predicted to respond to the SP1 inhibitor with a CANscript score of more than 25. This finding is in line with the percentage of SP1 sensitivity seen in other cancers. While the SP1 level was not consistently elevated in this subset, stem cell markers like NANOG, BMI1 and CD133 were found to be differentially expressed in selected cases. An association of resistance and hypomethylation of MGMT was also found with SP1 pertubation was found. A significant subset of glioblastomas may display dependency on SP1driven pathways and inhibitors that target this pathway have the potential to positively impact treatment of this subset of tumors. Predicting clinical response to anticancer drugs using an ex vivo platform that captures tumour heterogeneity. Majumder B, et.al
Elotuzumab plus Pomalidomide and Dexamethasone for Multiple Myeloma
Authors: Meletios A. Dimopoulos, Dominik Dytfeld, Sebastian Grosicki, Philippe Moreau, Naoki Takezako, Mitsuo Hori, Xavier Leleu, Richard LeBlanc, Kenshi Suzuki, Marc S. Raab, Paul G. Richardson, Mihaela Popa McKiver, Ying-Ming Jou, Suresh G. Shelat, Michael Robbins, Brian Rafferty, Jesús San-Miguel
Journal: New England Journal of Medicine (2018)

The immunostimulatory monoclonal antibody elotuzumab plus lenalidomide and dexamethasone has been shown to be effective in patients with relapsed or refractory multiple myeloma. The immunomodulatory agent pomalidomide plus dexamethasone has been shown to be effective in patients with multiple myeloma that is refractory to lenalidomide and a proteasome inhibitor.Patients with multiple myeloma that was refractory or relapsed and refractory to lenalidomide and a proteasome inhibitor were randomly assigned to receive elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone alone (control group). The primary end point was investigator-assessed progression-free survival.A total of 117 patients were randomly assigned to the elotuzumab group (60 patients) or the control group (57 patients). After a minimum follow-up period of 9.1 months, the median progression-free survival was 10.3 months in the elotuzumab group and 4.7 months in the control group. The hazard ratio for disease progression or death in the elotuzumab group as compared with the control group was 0.54 (95% confidence interval [CI], 0.34 to 0.86; P=0.008). The overall response rate was 53% in the elotuzumab group as compared with 26% in the control group (odds ratio, 3.25; 95% CI, 1.49 to 7.11). The most common grade 3 or 4 adverse events were neutropenia (13% in the elotuzumab group vs. 27% in the control group), anemia (10% vs. 20%), and hyperglycemia (8% vs. 7%). A total of 65% of the patients in each group had infections. Infusion reactions occurred in 3 patients (5%) in the elotuzumab group.Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-3 ClinicalTrials.gov number, NCT02654132 .).
A cell penetrating ARF peptide inhibitor of the Foxm1 transcription factor is an effective treatment for hepatocellular carcinoma in vivo
Authors: Robert H. Costa, Galina A. Gusarova, I-Ching Wang, Michael L. Major, Vladimir V. Kalinichenko, Timothy Ackerson, Vladimir Petrovic
Journal: Cancer Research (2006)

1445  The mammalian Forkhead Box (Fox) family of transcription factors consists of more than 50-mammalian proteins that share homology in the winged helix DNA binding domain. Expression of the Foxm1 transcription factor is ubiquitous in all proliferating mammalian cells and tumor derived cell lines where it regulates expression of cell cycle genes critical for DNA replication and mitosis. We previously used the Albumin Promoter/Enhancer Cre Recombinase (Alb-Cre) transgene to mediate hepatocyte-specific deletion of the mouse Foxm1 fl/fl targeted allele prior to hepatic tumor induction by Diethylnitrosamine (DEN)/Phenobarbital (PB) treatment. Foxm1 deficient (-/-) hepatocytes failed to proliferate and were resistant to development of hepatocellular carcinomas (HCC) in response to DEN/PB exposure. Furthermore, Foxm1 activity is inhibited by a cell penetrating peptide corresponding to amino acids 26 to 44 of the ARF tumor suppressor protein fused to nine D-Arginine (D-Arg) residues. In this study, we used the Interferon a/b-inducible Mx-Cre transgene to conditionally delete the Foxm1 fl/fl allele in preexisting mouse liver tumors induced by DEN/PB treatment and genetically demonstrated that Foxm1 is required for proliferation of hepatic tumor cells during tumor progression. To reduce in vivo function of Foxm1 in HCC, mice were subjected to daily intraperitoneal injections with a cell penetrating wild type (D-Arg)9 ARF 26-44 (WT ARF 26-44) peptide. After 4 weeks of WT ARF 26-44 peptide treatment, HCC regions displayed reduced proliferation and capillary development and a significant increase in HCC apoptosis without inducing damage to the adjacent normal liver tissue. This selective apoptosis correlated with a 90% reduction in levels of the anti-apoptotic survivin protein and was independent of the p53-PUMA transcriptional pro-apoptosis pathway. In contrast, no effect on proliferation, apoptosis or capillary development of HCC was found in mice treated with the cell penetrating mutant (D-Arg)9 ARF 37-44 (Mut. ARF 37-44) peptide, which was missing sequences necessary to interact with the Foxm1 protein. Furthermore, the WT ARF 26-44 peptide was able to induce apoptosis in human hepatoma HepG2 cells in vitro. This HepG2 cell apoptosis correlated with diminished expression of the mitotic regulatory proteins polo-like kinase 1 (PLK1), aurora B kinase and survivin, which are transcriptional targets of FoxM1 that are highly expressed in cancer cells and function to prevent apoptosis. These studies indicate that the WT ARF 26-44 peptide is effective in limiting HCC tumor progression by selectively inducing liver tumor apoptosis, and therefore, this peptide can be used for HCC treatment in human patients.
Abstract 18260: High Right Ventricular Stroke Work Index is Associated With Worse Kidney Function in Patients With Heart Failure With Preserve Ejection Fraction
Authors: Napatt Kanjanahattakij, Natee Sirinvaravong, Francisco Aguilar, Akanksha Agrawal, Parasuram Krishnamoorthy, Shuchita Gupta
Journal: Circulation (2017)

Background: In patients with heart failure with preserved ejection fraction (HFpEF), worse kidney function is associated with worse overall cardiac mechanics. The direct relationship between right ...
Determination of EGFR and Her2/neu protein expression by immunohistochemistry and EGFR gene status by fluorescence in situ hybridization in high-grade glioma
Authors: Jan Sadones, Alex Michotte, Peter In ’t Veld, Cristo Chaskis, Raf Sciot, Johan Menten, Eric J. R. Joosens, Theo Strauven, Marleen V. Borms, Guy Storme, Jacques De Grève, Bart Neyns
Journal: Cancer Research (2005)

4869  Background: The EGFR (Epidermal Growth Factor Receptor) and Her2/neu genes play an important role in cancer pathogenesis and biology. Amplification of the EGFR gene has been described in 20-40% of high-grade gliomas. Targeted anti-cancer agents (e.g. trastuzumab, erlotinib, gefitinib, lapatinib) have become available that inhibit these proto-oncogenes. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests are commercially available to determine the expression and amplification status of both genes. This study aimed to determine the usefulness of IHC and FISH and to establish the correlation between both tests for both these genes in a cohort of high-grade glioma. This knowledge should be of help to stratify glioma patients in clinical trials with targeted agents against EGFR or Her2/neu. Material and methods: Tumor tissues from 63 patients were collected from a retrospective cohort of patients from five different Belgian hospitals. In addition to conventional histopathology, tumors were characterized by IHC for expression of the EGFR (DAKO EGFR pharmDX) and Her2/neu (DAKO HercepTest) and by FISH for the amplification status of the EGFR gene (Vysis, LSI EGFR/CEP 7 Dual Color Probe). Results: The patient population (n = 63) consisted of 40 men and 23 women with a median age of 55 years at diagnosis. According to WHO classification, there were 17 anaplastic astrocytoma (AA) and 46 glioblastoma multiforme (GBM). None of the glioma in this series expressed Her2/neu and therefore this cohort was not further explored with FISH for Her2/neu gene amplification. FISH identified an amplification of the EGFR gene in 4/17 AA (23,5%) and 15/46 GBM (32,6%). Interpretation of FISH results was straightforward. A positive EGFR IHC staining was observed in 12/17 AA (70,6%) and 39/46 GBM (84,8%) when a cut-off of 10% positive cells with membrane staining was taken into account. EGFR gene amplification did not correlate with the level of expression assessed by IHC staining. Conclusions: The Her2/neu proto-oncogene is not expressed in AA and GBM and therefore this gene seems not involved in the biology of high-grade glioma. We confirmed that EGFR is expressed in most AA and GBM and that the EGFR gene is frequently amplified in these tumors. EGFR IHC was not correlated with EGFR gene amplification status as determined by FISH. Stratification of glioma patients in clinical trials according to EGFR FISH results seems feasible and preferable as compared to IHC.
PARP1 inhibition selectively radiosensitized malignant gliomas with hyperactive EGFR
Authors: Clark Chen, Richard Kennedy, Santosh Kesari, Alan D'Andrea
Journal: Cancer Research (2008)

428   Despite recent advances in the treatment of malignant gliomas, it remains one of the deadliest of cancers, resulting in lethality in nearly all affected patients. Radiation therapy is a critical component of the treatment regimen for this disease. However, due to tumor resistance, recurrence is a frequent phenomenon. Development of agents aimed to abridge this resistance should augment the efficacy of radiation therapy.  Ideally, such an agent should act selectively on the tumor relative to the normal cells. Since the tumor state is defined by genetic changes, including oncogenic activation and tumor suppressor inactivation, tumor specificity translates into targeting cell states imposed by these genetic changes. To this end, we set out to identify SiRNAs that cause selective radiation sensitization of glioma cell lines over-expressing tumor pertinent oncogenes relative to isogenic cell lines without such over-expression.  To minimize the likelihood of cell line specific artifacts, two isogenic glioma lines were used: the U87/U87+EGFRvIII pair and the THV/THV+H-Ras V12G  pair. EGFRvIII is an oncogenic variant of the Epidermal Growth Factor Receptor (EGFR) where an in-frame deletion of exons 2-7 results in constitutive receptor activation. This variant is found in 30-50% of high-grade gliomas. The H-Ras V12G  oncogene was selected because a significant portion of the aberrant EGFRvIII signaling has been attributed to H-Ras hyper-activation.  We screened a commercially available library (QIAGEN) consisting of 712 SiRNAs directed against 356 genes implicated in DNA repair/damage response. We first identified SiRNA that radiosensitized both the U87+EGFRvIII and the THV+H-Ras V12G  cell lines. Top SiRNAs were divided into five groups based on the function of the target gene. Representative target genes from each group (PARP1, CDK7, RPA3, FANCF, or HDAC1) were subsequently characterized. These analyses revealed that SiRNA silencing of PARP1 and CDK7, but not of RPA3, FANCF, or HDAC1, preferentially sensitized gliomas over-expressing EGFRvIII or H-Ras V12G  relative to their isogenic counterparts without oncogenic over-expression. To exclude “off-target effects”, we showed that treatment with a specific PARP1 inhibitors, 3-aminobenzamide (Sigma) and NU1025 (Sigma), recapitulated the selective radiosensitizing effects of PARP1 silencing. Silencing of CDK7, RPA3, FANCF, and HDAC1, but not PARP1, augmented the radiosensitizing effects of 3-aminobenzamide (Sigma), suggesting rationale for combination therapy.  These results offer pre-clinical evidence that PARP1 inhibition may serve to augment the efficacy of radiation therapy in malignant glioma treatment. Moreover, it defines EGFR and H-RAS hyperactivation as molecular determinants of therapeutic response - an observation that must be taken into consideration in clinical trial design.
Phase III Trial of Adjuvant Sunitinib in Patients with High-Risk Renal Cell Carcinoma: Exploratory Pharmacogenomic Analysis
Authors: Daniel J. George, Jean-Francois Martini, Michael Staehler, Robert J. Motzer, Ahmed Magheli, Frede Donskov, Bernard Escudier, Sherry Li, Michelle Casey, Olga Valota, Brigitte Laguerre, Allan J. Pantuck, Hardev S. Pandha, Anup Patel, Maria Lechuga, Alain Ravaud
Journal: Clinical Cancer Research (2018)

Abstract Purpose: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. Patients and Methods: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted. Results: In all, 286 patients (sunitinib, n = 142; placebo, n = 144) were genotyped. Longer DFS [HR; 95% confidence interval (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44; 95% CI, 0.21–0.91; P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46; 95% CI, 0.23–0.90; P = 0.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30–0.94; P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies (P ≤ 0.05), and A/A versus C/C with sunitinib (P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P = 0.038) and combined (P = 0.006) groups. Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.
ATIM-26. IMMUNOLOGIC TRENDS ASSOCIATED WITH PATIENT OUTCOMES IN A PHASE 1 CLINICAL TRIAL OF TOCA 511 AND TOCA FC IN RECURRENT HIGH GRADE GLIOMA
Authors: William Accomando, Timothy Cloughesy, Steven Kalkanis, Tom Mikkelsen, Joseph Landolfi, Bob Carter, Clark Chen, Michael Vogelbaum, James Elder, David Piccioni, Tobias Walbert, Daniel Hogan, Oscar Diago, Dawn Gammon, Ali Haghighi, Thian Kheoh, Harry Gruber, Douglas Jolly, Derek Ostertag
Journal: Neuro-Oncology (2018)

Toca 511 (vocimagene amiretrorepvec) is a cancer selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5- fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Preclinical evidence demonstrates that the Toca 511 & Toca FC regimen kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to durable antitumor immune responses that can be adoptively transferred to untreated animals. In an ascending dose trial (NCT01470794) in patients with recurrent high grade glioma (rHGG), Toca 511 was injected into the resection cavity walls at the time of resection, and then multiple courses of oral Toca FC were administered. Multiyear durable and complete responses by independent radiology review have been reported. Human immune monitoring results support an immunologic mechanism of action and identify potential biomarkers related to patient outcomes. Measurements included the quantification of peripheral blood and tumor infiltrating leukocyte subsets by flow cytometry, immunohistochemistry, and deconvolution of DNA and RNA sequencing data. In addition, systemic cytokine levels were assessed in peripheral blood serum by multiplex digital ELISA. Univariate comparisons and multivariate models revealed immunologic trends associated with patient outcomes. Pre-treatment tumor infiltrating cell subsets, quantified via deconvolution of RNA sequencing data, were associated with both objective responses and survival. Subsequent exploratory models applied to selected patient data indicate that a combined biomarker using mRNA signatures from multiple leukocyte subsets may predict patient outcomes with high sensitivity and selectivity. In addition, post-treatment serum cytokine time-course results suggest that differences and temporal modulations are associated with both objective response and survival. These results support an immune-related mechanism of action for the Toca 511 & Toca FC regimen. Potentially predictive and/or prognostic biomarkers of patient outcomes will be evaluated in the ongoing randomized Phase 3 Toca 5 trial in patients with rHGG (NCT02414165).