tbuckley/cabot-search huggingface dataset:
Palonosetron (PALO) versus granisetron (GRA) in the triplet regimen with dexamethasone (DEX) and aprepitant (APR) for preventing chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC) with cisplatin (CDDP): A randomized, double-blind, phase III trial.
Authors: Hironobu Hashimoto, Takeharu Yamanaka, Yasuhiro Shimada, Koji Arata, Reiko Matsui, Koichi Goto, Tomomi Takiguchi, Fumiyoshi Ohyanagi, Yuki Kogure, Naoyuki Nogami, Masahiko Nakao, Koji Takeda, Kanako Azuma, Seisuke Nagase, Toshinobu Hayashi, Kimiko Fujiwara, Toshikazu Shimada, Nobuhiko Seki, Kenichi Suzuki, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2013)

9621 Background: Standard antiemetic care for preventing CINV due to HEC is a combination of 5-HT 3 receptor antagonist (RA), DEX, and APR. This study compared the efficacy of two 5-HT 3 drugs, PALO and GRA, in the triplet regimen. Methods: Pts with a malignant solid tumor who were receiving HEC containing 50 mg/m 2 or more CDDP were enrolled. They were randomly assigned to either Arm A (PALO 0.75 mg, i.v.) or Arm B (GRA 1 mg, i.v.), 30 min before chemotherapy on day 1, both arms with DEX (9.9 mg on day 1 and 6.6 mg on day 2-4, i.v.) and APR (125 mg on day 1 and 80 mg on day 2–3, p.o.). Primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medications) at the overall (0-120 hours) phase. Secondary endpoints included CR at the acute (0-24 h) and delayed (24-120 h) phases, and total control (TC; no emetic episodes, no rescue medications, and no nausea) at the overall, acute, and delayed phases. The planned sample size of 840 provided 90% power to detect a 10% improvement in the CR at 0-120 h with two-sided alpha of 0.05. Primary analysis was conducted with exact Cochran-Mantel-Haenszel (CMH) test. Results: Between July 2011 and June 2012, 842 pts were enrolled and 827 were evaluable. The median CDDP dose was 76.1 mg/m 2 in Arm A and 75.7 mg/m 2 in Arm B. Baseline factors were well-balanced. Efficacy results are summarized in the Table. Conclusions: The present study did not meet its primary endpoint. However, it has shown that the clinical utility of PALO exceeds that of GRA. PALO is a more preferable 5-HT 3 RA in the triplet regimen than GRA in the prevention of CINV due to HEC. Clinical trial information: 000004863. [Table: see text]
Abstract 3018: Cotargeting MEK and CDK4/6 to treat pancreatic adenocarcinoma
Authors: Joel D. Maust, Diane Simeone, Judith Sebolt-Leopold
Journal: Cancer Research (2016)

Abstract Hyperactivation of KRAS and inactivation of CDKN2A [p16] play a prominent role in tumor initiation and progression in a broad spectrum of human cancers. In pancreatic adenocarcinoma, KRAS mutation occurs in 90-95% of cases and is often coupled with inactivation of CDKN2A (&amp;gt;90% incidence), typically by homozygous deletion. Based on the high incidence of these genetic events, the present study addresses the hypothesis that dual targeting of MEK and CDK4/6 represents a viable therapeutic strategy for the treatment of pancreatic adenocarcinoma. A panel of primary and high passage xenograft models was screened for in vitro synergy to the antiproliferative effects of the MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib. Two models that emerged as highly sensitive to this combination treatment strategy, L3.6pl and UM59, both exhibited G1 cell cycle arrest that was significantly more pronounced in response to the combination compared to either single agent. In vivo studies were subsequently carried out to evaluate the efficacy of this combination in tumor-bearing mice. Mice implanted subcutaneously with L3.6pl or UM59 cells were treated daily by oral gavage for ten days with trametinib (3 mg/kg), palbociclib (100 mg/kg), or the combination of these two agents at these doses. Consistent with in vitro synergy observations, both models proved to be exceptional responders in vivo to this combination treatment strategy, showing a robust response to the combination not seen with either single agent. These results suggest that the combined inhibition of MEK and CDK4/6 may offer a valuable therapeutic strategy for the treatment of pancreatic adenocarcinoma. Studies are ongoing to identify molecular determinants of response in pancreatic tumors that are highly sensitive to this combination approach to guide future patient enrichment strategies. Citation Format: Joel D. Maust, Diane Simeone, Judith Sebolt-Leopold. Cotargeting MEK and CDK4/6 to treat pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3018.
Abstract 2347: The amphiphatic β(2,2)-amino acid derivative, LTX-401 induces complete regression of experimental hepatocellular carcinomas
Authors: Brynjar Mauseth, Ji-Hua Shi, Ketil Camilio, Øystein Rekdal, Baldur Sveinbjørnsson, Pål-Dag Line
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and third cause of cancer-related deaths. Because HCC is a relatively chemotherapy-resistant cancer, and many patients are restricted to surgical resection or liver transplantation, there is an urgent need to develop new and improved therapeutic regiments. In the present study, we have investigated the therapeutic effect of a novel oncolytic compound, LTX-401, designed for the local treatment of solid malignancies. In vitro analysis revealed that LTX-401 displayed potent anticancer activity against a broad variety of cancer cell lines. In our model cell line (JM1 HCC), LTX-401 was found to induce necrotic (lytic) cell death followed by the release of potent immune stimulants in the form of Danger-Associated Molecular Pattern molecules (DAMPs) such as HMGB1 and ATP. Ultrastructural analysis by transmission electron microscopy also revealed that a substantial portion of LTX-401-treated JM1 cells contained significantly affected mitochondria. Additionally, cytochrome c was detected in cell supernatants after treatment. The anticancer effect of LTX-401 was investigated in a rat hepatocellular carcinoma model by inoculating JM1 cells into the liver (intrahepatic) of syngeneic Fischer 344 rats. LTX-401 induced a complete regression of HCC tumors by intratumoral injection. Tumor-specific protective immune responses were obtained in previously cured animals, as re-challenge with live and equivalent tumor cells did not lead to tumor growth. Furthermore, intratumoral treatment with LTX-401 was able to eradicate diffuse distant untreated metastasis in the liver. Immuno-histological analysis showed T-cell infiltration into treated tumors. Taken together, intrahepatic treatment with LTX-401 can induce complete regression and long lasting protective tumor-specific immune responses. Citation Format: Brynjar Mauseth, Ji-Hua Shi, Ketil Camilio, Øystein Rekdal, Baldur Sveinbjørnsson, Pål-Dag Line. The amphiphatic β(2,2)-amino acid derivative, LTX-401 induces complete regression of experimental hepatocellular carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2347.
Abstract 411: Sensitive detection of BRAF V600E mutation by bridged nucleic acid (BNA)-mediate real-time PCR assay
Authors: Xiaoyun Liu, Leticia Loredo, Houquan Dai, Aaron Castro, Yuewei Zhao, Sung Kun Kim, Austin Dinkel, Miguel Castro
Journal: Cancer Research (2016)

Abstract BRAF is a human gene encoding a serine/threonine protein kinase in the RAS-RAF-MEK-ERK signal pathway, which is important in regulating cellular responses to extracellular signals. Frequent mutations on BRAF gene have been detected in various types of human cancer, including malignant melanoma, non-small cell lung cancer, colorectal cancer, papillary carcinoma of the thyroid, ovarian cancer and hairy cell leukemia. Among all, a single point 1799T&amp;gt;A (V600E) transversion, the most common mutation on BRAF, results in increased kinase activity. It serves as a driver mutation in several types of cancer and confers increased sensitivity to tyrosine kinase inhibitors. Thus, detecting the BRAF V600E mutation may offer valuable information for cancer diagnosis, treatment selection, and prognosis. Here we report a rapid, highly sensitive method for the detection of BRAF V600 mutation using a bridged nucleic acid (BNA) clamp technology associated with quantitative PCR (qPCR). Due to the feature of enhanced affinity for hybridization template, BNA clamp is able to selectively block PCR reactions on the perfect match DNA sequence, while leaves the mismatch template unaffected. In this study several BNA clamps that bind to BRAF V600 wild-type (WT) template was designed, synthesized, and characterized. As compared to DNA clamp counterparts, these BNA clamps increased Tm values for the BRAF V600 WT by greater than 30°C. In addition, BNA clamps efficiently distinguished BRAF WT (perfect match) from V600E (mismatch) templates (deltaTm &amp;gt;12°C). In qPCR assays BNA clamps could suppress amplification of WT by &amp;gt;1,000-fold, while had little or no effects on the V600E mutant. Such BNA clamps allowed us to detect 1.0% or lower levels for the BRAF V600E mutant in a wild-type background. These results indicate that BNA clamp-based qPCR technology offers a new tool for rapid, sensitive detection of BRAF V600E mutation. The technology may be adapted for detection of mutations of a variety of biomarker genes. Citation Format: Xiaoyun Liu, Leticia Loredo, Houquan Dai, Aaron Castro, Yuewei Zhao, Sung Kun Kim, Austin Dinkel, Miguel Castro. Sensitive detection of BRAF V600E mutation by bridged nucleic acid (BNA)-mediate real-time PCR assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 411.
Ras-Pathway Inhibition With Targeted Therapies Abrogates Self-Renewal In Acute Myelogenous Leukemia
Authors: Rebecca S. LaRue, Hanh Nguyen, Karen Sachs, Nurul Azyan Mohd Hassan, Ernesto Diaz-Flores, Susan K. Rathe, Aaron G. Sarver, Sean C. Bendall, Ngoc A. Ha, Miechaleen D. Diers, Garry P. Nolan, Kevin Shannon, Zohar Sachs, David A. Largaespada
Journal: Blood (2013)
In vivo assessment of the effects of bevacizumab in advanced non-small cell lung cancer (NSCLC).
Authors: R. S. Heist, G. D. Duda, D. Sahani, N. A. Pennell, J. W. Neal, M. Ancukiewicz, J. A. Engelman, T. J. Lynch, R. K. Jain
Journal: Journal of Clinical Oncology (2010)

7612 Background: The addition of bevacizumab to chemotherapy for advanced NSCLC patients improves survival and demonstrates the benefit of antiangiogenic therapy in the treatment of lung cancer. However, the mechanism of anti-tumor activity is still poorly understood and thus it is unknown if the efficacy of this therapy is being maximized. Studies are needed to understand the mechanism of action and identify biomarkers for bevacizumab in NSCLC patients. Methods: Patients with previously untreated, non-squamous, advanced NSCLC were enrolled in an open-label phase II trial. All patients were given a single induction dose of bevacizumab 15 mg/kg at day -14 (14 days prior to starting combination therapy with carboplatin AUC 6 d1, nab-paclitaxel (abraxane) 100 mg/m2 d 1,8, 15, and bevacizumab 15 mg/kg d1, on a 21 day cycle). Correlative imaging and biomarker studies were performed with FDG-PET, perfusion CT, and blood for circulating cellular and molecular biomarkers, at the following timepoints: days -14 and -2 (prior to and 12 days after induction bevacizumab), and every two cycles on combination chemotherapy. Planned enrollment is 36 patients. Changes in biomarkers from day -14 to day -2 were tested using the paired Wilcoxon exact test, and correlations with best percent difference in RECIST measurements of response were tested using the Kendall's tau test. Results: Sixteen patients have been enrolled thus far. Bevacizumab alone significantly decreased circulating CD34+ progenitor cells (p < 0.01) and soluble c-KIT (p < 0.05). Mean blood flow (BF) and blood volume (BV) decreased from day -14 to -2 (p = 0.05 and 0.03, respectively). Of 12 patients evaluable for response to date, best confirmed response was 3 PR, 8 SD, and 1 PD. BF after bevacizumab alone correlated directly with the percent change in RECIST (Kendall's tau = 0.58 p < 0.01). Conclusions: Pharmacodynamic blood and imaging biomarker studies in bevacizumab-treated NSCLC patients are feasible and preliminary data suggest they may predict for tumor response. A complete biomarker analysis for these patients will be presented at the Meeting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gatekeeper, Infinity AstraZeneca, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dyax, MedImmune, Merck, Millennium, Regeneron, Roche, Schering-Plough, SynDevRx Infinity, SynDevRx Pfizer Abraxis BioScience, Genentech, Nereus Pharmaceuticals, Novartis
Abstract 4503: Actionable mutations and mutational burden in renal cell carcinoma
Authors: Susan M. Mockus, Sara E. Patterson, Jason R. Pettus, Gregory J. Tsongalis
Journal: Cancer Research (2016)

Abstract Clear cell renal cell carcinoma (CCRCC), the most common subtype of renal cell carcinoma, is a heterogeneous cancer with variable outcomes and molecular aberrations. Further elucidation of mutational profiles and actionable mutations may improve patient outcomes in CCRCC. Somatic mutational profiling via next-generation sequencing was conducted on 30 CCRCC whole section FFPE patient samples to determine the mutational burden as compared to other solid tumor types. The sequencing failure rate for these samples was 20% (6/30). A 358-gene panel was also run on an additional 57 non-CCRCC solid tumor FFPE patient samples (81 samples in total). FASTQ files generated from Illumina's CASAVA software were submitted to the JAX Clinical Genome Analytics (CGA) data analysis pipeline to perform automated read quality assessment, alignment, and variant calling. Identified variants were then submitted for clinical curation using the JAX Clinical Knowledgebase (CKB) for actionable mutational analysis and overall mutational burden. Of the CCRCC sample set, 33% had one or more actionable mutations. This was low compared to actionable mutations in colon (16/16, 100% actionable), TNBC (18/20, 90% actionable), squamous lung (8/9, 89% actionable), and pancreatic (8/12, 67% actionable). Furthermore, the CCRCC set had a low overall mutational burden with 22 ± 6.7 nonsynonymous SNV's as compared to colon (29 ± 11), squamous lung (43 ± 17), and TNBC (31.5 ± 12). However, the pancreatic set had even lower SNV's at 12.7 ± 3.4. The number of indels was comparable across the five sets, except for colon, which averaged 6.9 ± 8.3. Significant copy number variations (CNV’s; amplification validated at greater than or equal to 6 copies) also had a wide range with squamous lung at the highest (11 ± 11), followed by TNBC (5.6 ± 5.0), and then colon (2.3 ± 3.0). Both the CCRCC and pancreatic sets had few CNV's at 0.8 ± 1.5 and 0.17 ± 0.40, respectively. Common mutations identified in the CCRCC set included EPHB6 duplications near S166, which were identified in 25% of samples. Gene specific mutations in CCRCC were also identified in VHL (54%) and SETD2 (21%). These three genes, EPHB6, VHL, and SETD2 have been previously implicated in CCRCC pathogenesis. Six variants identified in VHL were C77*, P86R, Q132fs, A149D, R177fs, and L184fs. Due to the low mutational burden and/or actionable mutations in CCRCC, even large NGS panels may not be adequate to profile somatic mutations and whole exome or whole genome may be more conducive for molecular subtyping of renal cell carcinoma. Citation Format: Susan M. Mockus, Sara E. Patterson, Jason R. Pettus, Gregory J. Tsongalis. Actionable mutations and mutational burden in renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4503.
Genome-Wide DNA Copy Number Analysis by SNP Arrays of B-Cell Chronic Lymphocytic Leukemia: Correlation with Known Biological and Molecular Prognostic Markers.
Authors: Laura Mosca, Sonia Fabris, Giovanna Cutrona, Luca Agnelli, Serena Matis, Massimo Gentile, Mauro Spriano, Vincenzo Callea, Gianluca Festini, Stefano Molica, Caterina Mammi, Massimo Federico, Giorgio Lambertenghi Deliliers, Fortunato Morabito, Manlio Ferrarini, Antonino Neri
Journal: Blood (2008)
Part 10.6: Anaphylaxis
Journal: Circulation (2005)

AnaphylaxisA naphylaxis is a severe, systemic allergic reaction char- acterized by multisystem involvement, including the skin, airway, vascular system, and gastrointestinal tract.Severe cases may result in complete obstruction of the airway, cardiovascular collapse, and death.The term classic anaphylaxis refers to hypersensitivity reactions mediated by the subclass of antibodies immunoglobulins IgE and IgG.Prior sensitization to an allergen has occurred, producing antigen-specific immunoglobulins.Subsequent reexposure to the allergen provokes the anaphylactic reaction.Many anaphylactic reactions, however, occur without a documented prior exposure.Anaphylactoid or pseudoanaphylactic reactions display a similar clinical syndrome, but they are not immune-mediated.Treatment for the two conditions is similar. PathophysiologyThe inciting allergen binds to antigen-specific IgE that has accumulated on previously sensitized basophils and mast cells.These cells almost immediately release a series of mediators, including histamines, leukotrienes, prostaglandins, thromboxanes, and bradykinins.When released locally and systemically, these mediators cause increased mucous membrane secretions, increased capillary permeability and leak, and markedly reduced smooth muscle tone in blood vessels (vasodilation) and bronchioles.
The Case for Skin Cancer Screening With Total-Body Skin Examinations
Authors: Vinayak K. Nahar, Jonathan E. Mayer, Jane M. Grant-Kels
Journal: JAMA Oncology (2016)

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Abstract 1913: Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations
Authors: Rajgopal Govindarajan, Hardik Modi
Journal: Cancer Research (2016)

Abstract Identification of epigenetic reversal agents for use in combination chemotherapies for human pancreatic ductal adenocarcinomas remains an unmet clinical need. Pharmacological inhibitors of EZH2 are emerging as potential epigenetic reversal agents in various solid tumors and leukemia, however, the surprisingly small set of mRNA transcripts identified with EZH2 knockdown suggests novel mechanisms to govern their anti-tumorigenic effects. Here, we report 3-deazaneplanocin-A, an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, to significantly reprogram the noncoding miRNA expression, including a subset of PDAC-downregulated miRNAs, to dampen TGF-β-induced EMT signals in pancreatic cancer. Particularly, we identify epigenetic silencing of miR-663a and -4787-5p in PDAC tissues and cell lines that are reactivated by 3-deazaneplanocin-A to directly target TGF-β1 for RNA interference. Lentiviral overexpression of miR-663a and -4787-5p partially phenocopied 3-deazaneplanocin-A's EMT resisting effects in pancreatic cancer cells, whereas locked nucleic acid antimiR-663a and -4787-5p mitigated them. In vivo, 3-deazaneplanocin-A, miR-663a and -4787-5p significantly reduced tumor burden and metastasis in an orthotopic mouse pancreatic tumor model with miR-663a displaying more potency than miR-4787-5p in curtailing TGF-β1 signaling pathway. These findings reveal tumor miRNA reprogramming as a novel approach for controlling TGF-β-induced EMT in human PDAC and uncover a list of putative miRNA targets that may guide further selection and development of synthetic histone methylation reversal agents for clinical use. Citation Format: Rajgopal Govindarajan, Hardik Modi. Inhibition of S-Adenosylmethionine-dependent methyltransferase resists TGF-β1-induced EMT of pancreatic cancer via microRNA alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1913.
miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas
Authors: Shouwei Li, Ailiang Zeng, Qi Hu, Wei Yan, Yanwei Liu, Yongping You
Journal: Neuro-Oncology (2016)

Gliomas are based on a genetic abnormality and present with a dismal prognosis. MicroRNAs (miRNAs) are considered to be important mediators of gene expression in glioma tissues.Real-time PCR was used to analyze the expression of microRNA-423-5p (miR-423-5p) in human glioma samples and normal brain tissue. Apoptosis, cell cycle, proliferation, immunostaining, transwell, in vitro 2D and 3D migration, and chemosensitivity assays were performed to assess the phenotypic changes in glioma cells overexpressing miRNA-423-5p. Western blotting was used to determine the expression of inhibitor of growth 4 (ING-4)in glioma tissues, and a luciferase reporter assay was conducted to confirm whether ING-4 is a direct target of miR-423-5p. Western blotting was used to identify the potential signaling pathways that are affected in glioma cell growth by miR-423-5p. Xenograft tumors were examined in vivo for the carcinogenic effects of miR-423-5p in glioma tissues.We first reported that miR-423-5p expression was increased in gliomas and was a potential tumor promoter via targeting ING-4. The overexpression of miR-423-5p resulted in upregulation of important signaling molecules such as p-AKT and p-ERK1/2. In clinical samples, miR-423-5p was dysregulated, and a corresponding alteration in ING-4 expression was observed (P = .0207). Furthermore, the overexpression of miR-423-5p strengthened glioma cell proliferation, angiogenesis, and invasion. Finally, miR-423-5p overexpression also strengthened GBM neurosphere formation and rendered glioma cells resistant to temozolomide (TMZ).This study establishes that miR-423-5p functions as an oncogene in glioma tissues by suppressing ING-4 and suggests that it has therapeutic potential for glioma.
JRSM in a Brexit world
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2016)

Summer is here and brings a Brexit with it. The landscape for health and science in the UK feels vulnerable if you believe the warnings of our editorialists in a recent issue of JRSM.1 At times of vulnerability, we question our purpose. While Brexit creates no immediate issues for JRSM, what does the future hold?