tbuckley/cabot-search huggingface dataset:
High incidence of hypersensitivity reactions to cetuximab infusions in mid-Missouri: Association with prior history of atopy
Authors: R. Owera, A. Gill, S. Haddadin, R. Khozouz, M. C. Perry
Journal: Journal of Clinical Oncology (2008)

20747 Background: Epidermal growth factor receptors (EGFR) are overexpressed in several human solid tumors including colorectal cancer, head and neck cancer, non-small cell lung cancer, pancreatic cancer, and breast cancer. Cetuximab is a chimeric monoclonal antibody that is directed against EGFR. Infusion-related symptoms with fever, chills, urticaria, flushing,bronchospasm, dyspnea, angioedema, and hypotension, occur in 40%-50% of patients, although severe hypersensitivity reactions (grade III and IV) occur in less than 3%. A study from the University of North Carolina and the Vanderbilt Ingram Cancer Center found that the overall rate of grade 3 or 4 hypersensitivity reactions (HSR) was 22%, much higher than the reported national and international average of less than 3%. Methods: The study was approved by the University of Missouri-Columbia IRB (Project Number: 1097360). Data were collected from 65 patients treated with Cetuximab at Ellis Fischel Cancer Center between 2004 and 2007. The majority of patients had head and neck cancers (40/65–61.5%), followed by colorectal (20/65–30.76), then pancreatic (2/65–3%), and unknown primary (3/65–4.6%). Results: Eighteen patients (16/65–24.6%) developed grade III or IV reactions, twenty two patients (22/65–33.8%), had grade I or II reactions and twenty seven patients (27/65–41.5%) reported no reactions. A history of atopy was defined as a history of asthma, eczema, food allergy, H1 antagonist use, or severe drugs allergy (excluding narcotics). Twenty two patients (22/65–33.8%) were classified as having history of atopy; eight of the sixteen grades III or IV reactions occurred in patients with history of atopy (8/22), and the other eight occurred in patients with no prior history of atopy (8/43). Conclusions: Grade III or IV hypersensitivity reactions to Cetuximab infusion at the Ellis Fischel Cancer Center (24.6%) are higher than the reported national average (less than 3%) and are consistent with prior reports from neighboring states in the Midwest and southeast regions. Patients with a prior history of atopy have a higher incidence of hypersensitivity reactions to Cetuximab infusion, although the absence of atopy does not preclude the possibility of an HSR. No significant financial relationships to disclose.
Abstract 4736: PDE10A overexpression in cancer cells and tumors as compared to normal cells and tissues
Authors: Ashley S. Lindsey, Kevin Lee, Bing Zhu, Ritu Arora, Dennis Otali, Veronica Ramirez-Alacantara, William Grizzle, Gary Piazza
Journal: Cancer Research (2016)

Abstract Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme that is expressed in areas of the brain related to motor function and cognition. An elevation in neural PDE10A expression has been strongly linked to many diseases that affect cognition, including schizophrenia and Huntington's disease. Recently, high levels of PDE10A were shown to be expressed in colon tumor cells in vitro and in vivo compared with cells derived from normal colon and normal colonic mucosa (Li et al., Oncogene 2015). PDE10A inhibition by small molecules or genetic silencing, attenuated tumor cell growth by a mechanism involving cGMP/PKG activation, the suppression of β-catenin and a decrease in TCF transcriptional activity (Li et al., Oncogene 2015). These observations suggest that PDE10A may play an important role in tumorigenesis and PDE10A could serve as a novel therapeutic target for colorectal cancer. However, the expression and role of PDE10A in other cancer cell types has yet to be elucidated. Here we report that PDE10A expression is elevated (compared to controls) in tumor cells and solid tumors from xenograft, as well as, genetic models from the colon, breast, and lung using western blot and immunohistochemistry. The human colon adenocarcinoma cell line, HT29, the human breast adenocarcinoma cell line, MDA-MB-231, and the human lung carcinoma cell line, A549, showed elevated expression of PDE10A as compared to the normal colon mucosal epithelial cell line, NCM460, normal human mammary epithelial cells, and normal human airway epithelial cells, respectively. Solid tumors collected from the colons of heterozygous APCmin mice displayed an elevation in PDE10A levels as compared to uninvolved mucosa from the APCmin mice and wild type colon mucosa. Solid tumors collected from the mammary glands of viral transgenic FVB-MMTV-Her2 mice also possessed high levels of PDE10A as compared to FVB wild type mice. These findings suggest that PDE10A could be a novel therapeutic target for not only colorectal cancer, but breast and lung cancers as well. Citation Format: Ashley S. Lindsey, Kevin Lee, Bing Zhu, Ritu Arora, Dennis Otali, Veronica Ramirez-Alacantara, William Grizzle, Gary Piazza. PDE10A overexpression in cancer cells and tumors as compared to normal cells and tissues. [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 4736.
Correlating quantitative gene expression to radiologic response to docetaxel (DTX) in formalin-fixed paraffin-embedded (FFPE) tumor tissue from patients (pts) with metastatic non-small cell lung cancer (NSCLC)
Authors: C. G. Azzoli, N. Khokhar, J. Chen, E. Venkatraman, M. G. Kris, F. M. Sirotnak
Journal: Journal of Clinical Oncology (2004)

7030 Background: We hypothesized that TaqMan RT-PCR could be used to measure expression levels of individual genes in FFPE tumor samples, which might correlate with response to DTX (Taxotere™). Methods: We identified 140 pts who had received single-agent DTX for metastatic NSCLC, and had FFPE tissue available at our center. Radiologic response was determined according to standard criteria. We prepared an H&E slide from each block to verify that the tissue was nearly all tumor. A 40 micron slice was cut from the block, deparaffinized, deproteinized, RNA extracted using phenol/chloroform, and converted to cDNA. Based on published reports and proposed mechanisms of resistance to taxanes, we designed primers and probes to analyze the following genes: β-TUB1, β-TUB3, α-TUB1, α-TUB2, MRP1, MRP2, MRP4, MRP7, PGP, BCRP, LRP, GSTpi, BCL2, BCLxl, BAX, Survivin, MAD2, p53, transket, MAGE2, MCL1, HTERT, klf4, lklf, HER2, EGFR. Results: 53 blocks were identified as suitable for analysis. Of these, 32 blocks yielded RNA sufficient for TaqMan RT-PCR. Expression of the following genes was higher in pts with resistant disease: β-TUB3, p53, BAX, GSTpi, and HTERT (p<.05 by Jonckheere test for association). Of these, β-TUB3 showed the strongest association (p=0.014). Conclusions: FFPE tissue can be used to perform expression analysis of individual genes using high-throughput, TaqMan RT-PCR. These data justify a prospective trial to see whether the genes identified in this study predict resistance of NSCLC to DTX. This work was supported by Aventis Pharmaceuticals. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals Aventis Pharmaceuticals
Clinical Criteria to Identify Patients With Sepsis—Reply
Authors: Christopher W. Seymour, Derek C. Angus
Journal: JAMA (2016)

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Corrigendum to “Contamination of healthcare workers' mobile phones by epidemic viruses” [Clin Microbiol Infect (2016) 456.e1–456.e6]
Authors: S. Pillet, P. Berthelot, A. Gagneux-Brunon, O. Mory, C. Gay, A. Viallon, F. Lucht, B. Pozzetto, E. Botelho-Nevers
Journal: Clinical Microbiology and Infection (2016)
Abstract 293: EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity and thus inactivating Ets-1 function
Authors: Janyaporn Phuchareon, David W. Eisele, Frank McCormick, Osamu Tetsu
Journal: Cancer Research (2016)

Abstract In non-small-cell lung cancer (NSCLC)—the leading cause of cancer death worldwide—about 10-20% harbor mutations in epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Although treatment with EGFR tyrosine kinase inhibitors (TKIs) had shown promise, drug resistance has been the most important determinant limiting its success. Recent studies have identified the mechanisms of drug resistance to TKIs, but the origin of acquired resistant cells remains to be elucidated. We consider that they must arise from a small subset of surviving populations after EGFR inhibition. Thus, we have studied the mechanism by which the subset remains viable after EGFR inhibition, despite cell death in the vast majority. Our study demonstrates that EGFR inhibition in lung cancer cells generates a drug-tolerant subpopulation by blocking AKT activity and thus inactivating Ets-1 function. The remaining cells enter a dormant, non-dividing state because of the inhibited transactivation of Ets-1 target genes cyclins D1, D3, and E2. Moreover, Ets-1 inactivation inhibits transcription of dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated, which combines with c-Src to renew activation of the Ras/MAPK pathway, causing increased cell survival by accelerating Bim protein turnover. Conversely, inhibition of elevated ERK1/2 by the addition of a MEK inhibitor enhances programmed cell death through rewiring apoptotic signaling. These observations may explain why a small subset of quiescent cells can tolerate TKIs, and might suggest that combined treatment of TKI and MEK inhibitor could overcome drug resistance in the population. Citation Format: Janyaporn Phuchareon, David W. Eisele, Frank McCormick, Osamu Tetsu. EGFR inhibition generates drug-tolerant persister cells by blocking AKT activity and thus inactivating Ets-1 function. [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 293.
PWE-101 Imaging The Small Bowel In Ulcerative Colitis-relevant Or Still ‘’unclassified”?: Abstract PWE-101 Table 1
Authors: S Singh, D Aggarwal, JK Limdi
Journal: Gut (2014)

<h3>Introduction</h3> It is widely accepted that Ulcerative Colitis (UC) is a mucosal inflammatory disease confined to the colon. Bolder disease definitions coupled with novel and evolving imaging paradigms have led to more sophisticated small bowel imaging in recent years. Despite this, studies on the relevance and yield of small bowel pathology in UC patients are limited. <h3>Methods</h3> We conducted a retrospective review of consecutive UC patients seen at our institution between May-October 2013. Clinical data for demographics, disease characteristics, small bowel investigation, endoscopy, treatment and clinical outcomes were obtained from electronic patient records. <h3>Results</h3> We analysed 321 patients with biopsy confirmed UC [61% male, mean age 53 yrs, range 18–91 yrs]. Mean age of diagnosis was 43 yrs and mean disease duration was 10 yrs. Montreal classification was E1 (14%), E2 (49%) and E3 (37%) respectively. Forty-seven patients had small bowel investigations: MR enterography in 81%, CT enterography in 15% and barium follow-through in 4%. Disease severity at the time of small bowel imaging was mild to moderate in 68% and 32% had severe disease. Thirty-two percent of patients were on thiopurines, 19% on bimodal immunosuppression (infliximab + thiopurine) and 49% were on aminosalicylates. Seven patients had undergone colectomy. Small bowel imaging was reported normal in 46/47 and one patient had distal and terminal ileal disease. Indications for small bowel imaging are shown in Table 1. Subsequent to small bowel imaging, 40% (19/47) had no change in therapy, 43% were escalated to immunosuppressive therapy and 11% underwent surgery for UC. In 3 patients, the diagnosis was changed from UC to Crohn’s disease (2 with perianal Crohn’s; 1 with small bowel Crohn’s based on MRE) all subsequently treated with Anti-TNF therapy. <h3>Conclusion</h3> The yield of small bowel pathology in our cohort was low, supporting current European Crohn’s and Colitis Organisation (ECCO) recommendations.<sup>1</sup> Small bowel imaging in UC meanwhile should be considered in the well-selected patient and driven by the clinical question or diagnostic uncertainty. <h3>Reference</h3> Dignass A, Eliakim R, Magro F <i>et al</i>. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.<i> J Crohns Colitis</i>. 2012 Dec;6(10):965–90 <h3>Disclosure of Interest</h3> None Declared.
Smoking rates vary widely in US racial and ethnic groups
Authors: Michael McCarthy
Journal: BMJ (2016)

Smoking rates in US racial and ethnic groups can vary more than twofold between subgroups, a new study published by the US Centers for Disease Control and Prevention has found.1

The findings, CDC officials said, showed that smoking reduction efforts might be more effective if they targeted culturally appropriate interventions at those ethnic and racial subgroups with the highest prevalence of tobacco use. Bridgette Garrett, associate director for health equity in the CDC’s Office on Smoking and Health, said, “Looking beyond broad racial and ethnic population categories can help better focus the strategies that we know work to reduce tobacco use among subgroups with …
Abstract 3513: Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides
Authors: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Poonam Tewary, Curtis J. Henrich, Cheryl L. Thomas, A. A. Leslie Gunatilaka, Thomas J. Sayers
Journal: Cancer Research (2016)

Abstract We have previously reported that withanolide E (WE), a steroidal lactone from Physalis peruviana, was highly active in sensitizing various human carcinoma cell lines to TRAIL-mediated apoptosis. Treatment of cancer cells with WE induced a reduction in the levels of the antiapoptotic proteins cFLIPL and cFLIPS, resulting in an increased activation of caspase-8 on subsequent TRAIL binding to its death receptors DR4 or DR5. The reduction in cFLIPL and cFLIPS was due to their destabilization and increased degradation by the proteasome. Interestingly, WE (a 17-beta-hydoxywithanolide, 17-BHW) was a far superior TRAIL sensitizer than more widely studied withaferin A (WFA) and its analogues, which lack the 17-beta-hydroxy group and bear an opposite side chain orientation, exhibit more promiscuous reactivity and are much more directly toxic to cells. Therefore, over 30 natural and semi-synthetic 17-BHWs were evaluated for their ability to promote death ligand-mediated cancer cell death. The 17-BHWs used in this work were obtained by the application of an efficient method of plant biomass production involving our innovative and patented soil-less aeroponic cultivation of P. crassifolia and P. peruviana and by chemical modification of natural withanolides produced by these plants. Our studies identified several 17-BHWs that were 4-8 fold more potent than WE in sensitizing the renal carcinoma cells ACHN to TRAIL-mediated apoptosis. These more active 17-BHWs were also more efficient at reducing cellular levels of cFLIPL and cFLIPS and enhancing caspase-8 activation. Preliminary structure activity relationship (SAR) studies suggested that the enone moiety in ring A was essential for activity. In addition acetoxylation at C-18, an alpha orientation of the lactone group and the double bond at C-24(25) of the lactone ring played important roles in determining the activity of 17-BHWs as TRAIL sensitizers. This suggests that the 17-BHW scaffold is amenable to optimization by a medicinal chemistry approach, which could lead to the identification of highly active natural product-based sensitizers of cancer cells to TRAIL-mediated apoptosis. The cellular molecular target(s) of active 17-BHWs are currently under further investigation. Funded by FNLCR Contract HHSN261200800001E Citation Format: Alan D. Brooks, Ya-ming Xu, E. M. Kithsiri Wijeratne, Poonam Tewary, Curtis J. Henrich, Cheryl L. Thomas, A. A. Leslie Gunatilaka, Thomas J. Sayers. Promoting TRAIL apoptosis signaling using 17-beta-hydroxywithanolides. [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 3513.
Comprehensive characterization of 412 muscle invasive urothelial carcinomas: Final analysis of The Cancer Genome Atlas (TCGA) project.
Authors: Seth P. Lerner, Jaegil Kim, David J. Kwiatkowski, Gad Getz, John N. Weinstein, Andrew Cherniack, Guangwu Guo, Rehan Akbani, Katherine A. Hoadley, William Y. Kim, Gordon Robertson, Andrew J. Mungall, Toshinori Hinoue, Peter W. Laird, Hikmat Al-Ahmadie, Jonathan E. Rosenberg, Joaquim Bellmunt, Dean F. Bajorin, Donna E. Hansel, Chad J. Creighton
Journal: Journal of Clinical Oncology (2016)

405 Background: We reported the integrated molecular analysis of 131 tumors in 2014 (Nature 507:315, 2014) and now report on the entire cohort of 412 tumors from the TCGA project in chemotherapy-naïve muscle invasive urothelial bladder cancer. Methods: Following strict clinical and pathologic quality control, tumors were analyzed for DNA copy number variants, somatic mutations (WES), DNA methylation, mRNA, microRNA and (phospho-) protein expression, transcript splicing, gene fusions, viral integration, pathway perturbation, clinical correlates, and histopathology Results: There was a high overall somatic mutation rate (8.0/Mb), as previously reported, with a median of 245 and mean of 348 coding region mutations per sample. There were 54 significantly mutated genes (SMGs) (MutSig_2CV), increased from 32 in the original report. TP53 remained the most commonly mutated gene, and chromatin-modifying genes (MLL2, ARID1A, KDM6A) were also frequently mutated. KRAS, ERBB2, RB1, and ELF3 showed significant increased frequencies of mutation. High mutation burden was associated with improved outcome (p = 0.0004). APOBEC mutagenesis explained 70% of the mutation burden and also was associated with survival. 167 genes were silenced by promoter DNA hypermethylation in at least 5% of tumors. Several SMGs were also epigenetically silenced at various frequencies (ZNF773, CDKN2A, FAT1, CASP8). The previously identified four mRNA subtypes were predicted on the larger set identifying a similar proportion of samples in each subtype. We identified 5 expression subtypes based on reverse-phase protein arrays(344 tumors). Five miR expression subtypes were strongly associated with 4 mRNA-based subtypes (P = 3.8E-37) and associated with overall survival (P = 0.05). Conclusions: This integrated analysis of 412 TCGA patient samples validates and extends observations from the first 131 patients and significantly increases our power to detect additional low-frequency aberrations. The results provide a robust basis for functional studies to further our understanding of the biology of bladder cancer, and aid in the development of more precisely targeted therapies.
Abstract 5102: Heparan sulfate modifying enzymes deliver cancer, stromal and macrophage-produced heparin-binding growth factors in the prostate cancer microenvironment
Authors: Fabio H. Brasil, Valeria Ferrer, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson
Journal: Cancer Research (2016)

Abstract We previously showed that the heparan sulfate proteoglycan, perlecan (PLN)/HSPG2, is deposited into the matrix of reactive stroma surrounding tumors, where it concentrates heparin binding growth factors (HBGFs) and cytokines at the tumor-stromal border both in primary prostatic tumors and bone metastatic lesions. Heparan sulfate (HS) modifying enzymes produced in tumor-associated stroma play key roles in the delivery of these perlecan-sequestered cancer, stromal and tumor macrophage-produced HBGFs and cytokines, serving to enhance tumorigenesis and recruit other bystander cells to sites of metastasis. Studies presented here focused on the production of secreted HS-modifying enzyme heparanase and the two extracellular sulfatases, SULF1 and SULF2, in the prostatic tumor microenvironment. Our studies showed that SULF1 and heparanase mRNA levels are elevated in prostate cancer (PCa) cells of the LNCaP lineage in the presence of stroma, indicating that both stroma and PCa cells can be sources of these enzymes. We are presently examining a number of PCa patient derived xenografts to determine the prevalence of SULF-1 and heparanase elevation in castrate resistant disease. To study function, we developed a modified 3D hyaluronate gel system that contains HS-bearing recombinant perlecan domain I (PlnDI) to retain and deliver HBGFs and cytokines to various PCa cells cultured with bone marrow stromal cells, osteoblasts, or tumor macrophages. We are using this system to study the expression and individual functions of heparanase and the two SULFs in promoting HBGF-dependent PCa progression in a physiologically relevant system. Overexpression and gene deletion techniques allow us to determine the role that heparanase or SULFs play in each relevant cell type present in the tumor microenvironment, and thus determine the need for co-targeting of both tumor and reactive stroma. (Supported by NIH P01 and CAPES). Citation Format: Fabio H. Brasil, Valeria Ferrer, Nora M. Navone, Mary C. Farach-Carson, Daniel D. Carson. Heparan sulfate modifying enzymes deliver cancer, stromal and macrophage-produced heparin-binding growth factors in the prostate cancer microenvironment. [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 5102.