tbuckley/cabot-search huggingface dataset:
Abstract 3769: Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial cell carcinoma
Authors: Leigh Williams, Rebecca Ellston, Dawn Trueman, Helen Musgrove, Linette Ruston, Brian Aquila, Elizabeth Pease, Stephanie Klein, Barry R. Davies
Journal: Cancer Research (2016)

Abstract Urothelial Cell Carcinoma (UCC) is the fifth most common cancer, but no new generation molecularly targeted therapies have been registered to treat this disease. Non muscle-invasive bladder cancer can be treated by systemic or intravesical dosing routes. However, the urothelium is one of the most formidable permeability barriers in nature, and may limit the penetration of small molecules into tumour tissue from the intravesical location. Inhibitors of mitosis, including spindle proteins such as Eg5, are attractive targets for cancer therapy, but their efficacy when dosed systemically is severely limited by bone marrow toxicities such as neutropenia and thrombocytopenia. AZ9814, a very potent and selective small molecule inhibitor of Eg5, induces apoptosis and inhibits proliferation of UCC cells in culture with a GI50 of &amp;lt; 1 nM. We have developed an orthotopic model of bladder cancer in the nude rat coupled with a programmable mini-pump system to continuously infuse AZ9814 into the bladder, and compared the therapeutic index of this delivery route with systemic dosing schedules using intraperitoneal injection and continuous subcutaneous infusion using an osmotic mini-pump. Continuous intravesical infusion resulted in severe bladder toxicity including hydropic degeneration and ulceration of urothelium, mucosal erosion and bilateral hydronephrosis, with limited penetration of compound into the tumour, and no significant impact on tumour pharmacodynamics and growth. In contrast, continuous low intensity systemic dosing resulted in significant tumour pharamacodynamic activity and control of tumour growth, albeit with significant but non-lethal effects on bone marrow toxicity. Daily intraperitoneal injection of AZ9814 resulted in very modest anti-tumour effects which were limited by bone marrow toxicity. It is concluded that Eg5 inhibitors have potential to treat UCC, but continuous systemic infusion is the best dosing schedule to maximize therapeutic index. Citation Format: Leigh Williams, Rebecca Ellston, Dawn Trueman, Helen Musgrove, Linette Ruston, Brian Aquila, Elizabeth Pease, Stephanie Klein, Barry R. Davies. Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial 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 3769.
Biological Explanation of Clinically Observed Elevation of TFPI Plasma Levels After Treatment with TFPI-Antagonistic Aptamer BAX 499
Authors: Michael Dockal, Robert Pachlinger, Rudolf Hartmann, Sabine Knappe, Benny Sorensen, Wing Yen Wong, Maureen Conlan, Michael Cecerle, Bruce M. Ewenstein, Hartmut J. Ehrlich, Friedrich Scheiflinger
Journal: Blood (2012)
Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus
Authors: Albert L. Siu
Journal: Annals of Internal Medicine (2016)

Letters2 August 2016Screening for Abnormal Blood Glucose and Type 2 Diabetes MellitusAlbert L. Siu, MD, MSPHAlbert L. Siu, MD, MSPHFrom U.S. Preventive Services Task Force, Rockville, Maryland.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0102 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:The U.S. Preventive Services Task Force recommends screening for abnormal blood glucose levels as part of cardiovascular risk assessment in asymptomatic adults aged 40 to 70 years who are overweight or obese. The Task Force focused on this population because the available evidence suggests that the benefits of screening and treatment with lifestyle interventions exceed the potential harms in this group.Drs. Barkoudah and Weinrauch suggest that evidence may be insufficient to confidently determine whether the benefits of screening may be larger. We agree that currently available screening trials are inadequate and call for larger studies that measure ... Author, Article, and Disclosure InformationAffiliations: From U.S. Preventive Services Task Force, Rockville, Maryland.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2345. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoScreening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus: U.S. Preventive Services Task Force Recommendation Statement Albert L. Siu and Screening for Abnormal Blood Glucose and Type 2 Diabetes Mellitus Ebrahim Barkoudah and Larry A. Weinrauch Metrics Cited byContributions of Glucose and Hemoglobin A1c Measurements in Diabetes ScreeningIncreased risk of diabetes mellitus five years after an episode of Staphylococcus aureus bacteraemiaPrevalence of Obesity, Prediabetes, and Diabetes in Sexual Minority Men: Results From the 2014 Behavioral Risk Factor Surveillance SystemMetabolically Healthy Obese and Incident Cardiovascular Disease Events Among 3.5 Million Men and Women 2 August 2016Volume 165, Issue 3Page: 225KeywordsBloodDisclosureGlucoseMorbidityMortalityOverweightRisk assessmentsType 2 diabetes ePublished: 2 August 2016 Issue Published: 2 August 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Stimulation of Adrenergic Activity By Desipramine Enhances Hematopoietic Stem and Progenitor Cell Mobilization Along with G-CSF in Multiple Myeloma - a Pilot Study of Safety and Efficacy
Authors: Aditi Shastri, Ira Braunschweig, Stefan Klaus Barta, Noah Kornblum, Olga Derman, Ramakrishna Battini, Amit Verma, Paul S. Frenette, Murali Janakiram
Journal: Blood (2015)
Diagnostic Usefulness of JAK2 Mutation in Manistest or Latent Polycythemia Vera and Secondary Polycythemia.
Authors: Soo-Mee Bang, Eun Mi Nam, Jeong Yeal Ahn, Jae-Hoon Lee, Bong-Seog Kim, Seung-Hyun Nam, Hyun-Sook Chi, Young Uk Cho, Hyo Jung Kim, Dae Young Zang, Moo-Rim Park, Hyeok Shim, Jong Seok Lee, Jong-Ho Won, Doyeun Oh
Journal: Blood (2006)
Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial
Authors: Brian I Rini, Tanya B Dorff, Paul Elson, Cristina Suarez Rodriguez, Dale Shepard, Laura Wood, Jordi Humbert, Linda Pyle, Yu-Ning Wong, James H Finke, Patricia A Rayman, James M G Larkin, Jorge A Garcia, Elizabeth R Plimack
Journal: The Lancet Oncology (2016)
Abstract 2214: GITR ligand fusion protein (GITRL-Fc) induces T cell mediated anti-tumor immune response and can combine with anti-PDL1 to enhance anti-tumor immunity and long-term immune memory
Authors: Minu K. Srivastava, Rui Yun, Erin Mayes, Hyun_Bae Jie, Fumiko Axelrod, Jorge Monteon, Ming-Hong Xie, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park
Journal: Cancer Research (2016)

Abstract GITRL (Glucocorticoid-Induced Tumor Necrosis Factor Receptor Ligand, TNFSF18) is a member of the TNF superfamily and naturally exists as a membrane-anchored type II protein that self assembles as a trimer. GITRL activates the co-stimulatory receptor GITR. GITR is found primarily on activated T effector (Teff) cells and regulatory T (Treg) cells. Co-stimulation of GITR by agonist agents is hypothesized to promote anti-tumor immunity by enhancing Teff cell activity and inhibiting Treg suppression. We generated a novel single-gene GITRL trimer fused to an immunoglobulin Fc domain (GITRL-Fc). GITRL-Fc activated GITR signaling more effectively than prototype GITR agonist antibody DTA-1. GITRL-Fc promoted a robust anti-tumor immune response in multiple syngeneic mouse tumor models. GITRL-Fc enhanced tumor specific T-cell responses, particularly of the Th1 type, and also led to reduction in Treg-mediated immunesuppressive activity. GITRL-Fc displayed single agent activity in inhibiting tumor growth and promoting complete tumor rejection in the murine CT26 colon carcinoma model and combination activity with anti-PDL1 as compared to anti-PDL1 and control IgG2a alone. Mice “cured” with GITRL or GITRL/anti-PDL1 combination treatments were protected from re-challenge with tumor cells, suggesting the existence of immunologic memory. More mice were protected from tumor re-challenge with the combination of GITRL-Fc and anti-PDL1, as compared to GITRL-Fc alone. Our results demonstrate that agonist GITRL-Fc induces potent T cell responses, overcomes Treg inhibition, and promotes anti-tumor activity in preclinical models as a single agent or in combination with anti PDL1. The mechanism of tumor eradication and induction of long-term immune memory response by the combination is under investigation and will be discussed at the presentation. Citation Format: Minu K. Srivastava, Rui Yun, Erin Mayes, Hyun_Bae Jie, Fumiko Axelrod, Jorge Monteon, Ming-Hong Xie, John Lewicki, Tim Hoey, Austin Gurney, Angie Inkyung Park. GITR ligand fusion protein (GITRL-Fc) induces T cell mediated anti-tumor immune response and can combine with anti-PDL1 to enhance anti-tumor immunity and long-term immune memory. [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 2214.
Abstract 2255: Evaluation of the diagnostic value of serum anti-cyclin B1 autoantibody as a biomarker in lung cancer
Authors: Mengtao Xing, Pei Li, Jianxiang Shi, Liping Dai, Jitian Li, Jianying Zhang
Journal: Cancer Research (2016)

Abstract To detect the diagnostic value of cancer-associated autoantibodies in lung cancer, a panel of 9 tumor-associated antigens (TAAs) were used in this study. The TAAs were composed of p62, p16, Koc, p53, Cyclin B1, Cyclin E, Survivin, HCC1, and Rol-A full-length recombinant proteins. Enzyme-linked immunosorbent assay and immunoblotting were used to detect antibodies in 50 lung cancer sera with clinicopathological characteristics and 42 sera from normal individuals. Following, antibodies to Cyclin B1, survivin, p53 and HCC1 were selected and confirmed in another 62 sera from patients with lung cancer but without clinical date and evaluate the diagnostic value of these TAAs. The results showed that the positive rate of autoantibodies against nine selected TAAs (cyclin B1, survivin, HCC1,p53, KOC,p16,p62, RalA and cyclin E) reached 36%, 36%, 26%, 12%, 8%, 6%, 6%, 2%, 0% in 50 lung cancer sera and 4.8%, 2.4%, 0%, 0%, 2.4%, 4.8%, 2.4%, 2.4%, 4.8% in 42 normal sera, respectively. The AUC values for distinguishing lung cancers from normal sera were 0.767, 0.400, 0.567, 0.395, 0.230, 0.517, 0.635, 0.194, 0.411, respectively. These data suggest that cyclin B1, survivin, HCC1 and p53 has higher clinical diagnostic quality and value than other TAAs in lung cancer. In the confirmation group with 62 lung cancer sear, autoantibodies against these four TAAs were also significantly higher in patients with lung cancer (AUC values of 0.764,0.653,0.623 and 0.622, p&amp;lt;0.05). Evaluation of the diagnostic value of these four TAAs in 50 sera from lung cancer patients with clinical characteristics, and results revealed that serum anti-cyclin B1, anti-survivin and anti-p53 autoantibodies significantly increased in patients with stage I but only serum anti-cyclin B1 increased in stage II and III lung cancer (p &amp;lt;0.05, respectively), ROC curve analysis has shown that anti-cyclin B1 and anti-p53 autoantibodies can discriminate stage I lung cancer from normal controls with AUC value of 0.757,0.697, respectively (p&amp;lt;0.01), and anti-survivin and anti-HCC1 autoantibodies failed to discriminate stage I lung cancer from normal controls. Our results suggest that these four TAAs has higher clinical diagnostic quality and value than other TAAs in lung cancer and serum cyclin-B1 may have the potential to serve as novel non-invasive diagnostic biomarkers in patients with lung cancer, especially in early stage lung cancer. Citation Format: Mengtao Xing, Pei Li, Jianxiang Shi, Liping Dai, Jitian Li, Jianying Zhang. Evaluation of the diagnostic value of serum anti-cyclin B1 autoantibody as a biomarker in lung cancer. [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 2255.
Abstract 2546: With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs
Authors: Hakan L. Olsson
Journal: Cancer Research (2016)

Abstract Hereditary cancer that has monogenic inheritance affects every tenth patient, on average, who is diagnosed with cancer, and it has been suggested based on twin studies, that approximately 30% of all cancer patients have a genetic predisposition to developing cancer. The author posited that familial syndromes become more organ specific with increasing age at tumour presentation to the point that very late in life, only a few organs are affected by tumours disease. The reason for this could be that the tumour originates from a more differentiated, organ-specific progenitor/stem cell later in life, while the progenitor/stem cell might be involved in organogenesis in different organs earlier in life. Examples are given for skin cancer and breast cancer. Summary: Patients with familial cancer who present with cancer at an older age at tumour presentation have a more organ restricted disease. This could be because the tumor has a more differentiated progenitor/stem cell origin. Examples are given for families with breast cancer, melanoma, and non- melanoma skin cancer. References: Olsson H. A hypothesis about tumour development and the clinical features of hereditary cancer. European Journal of Cancer 2001 2023-2029. Olsson H. With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs. Journal of Cancer and Therapy (in press). Examples of the median age at diagnosis for melanoma (*) and breast cancer (**) in familial settingsFamilies with melanoma. CDKN2A positive melanoma cases. (melanoma, pancreas, smoking associated cancer)39*Families with melanoma. CDKN2A negative melanoma cases. (melanoma and skin cancer)48*Four or more tumors in the cancer registry, at least one of which is a melanoma. Multiple melanoma cases with other tumors and CDKN2A mutations.60*Four or more tumors in the cancer registry, at least one of which isa melanoma. Melanoma, other tumours and adenocarcinomas.67*Four or more tumors in the cancer registry, at least one of which is a melanoma. Melanoma and skin cancer.78*Li Fraumeni's syndrome&amp;lt;40**BRCA144**BRCA245**BRCAX (majority breast only families)48**Vertical inheritance52**Horizontal inheritance (possible recessive inheritance, breast cancer only families).63** Citation Format: Hakan L. Olsson. With increasing age at tumor diagnosis in families with cancer, cancer is limited to fewer organs. [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 2546.
Case 21-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Pierce Gardner, Stanley J. Robboy
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 71-year-old man was admitted to the hospital because of fever.He was well until three months previously, when anorexia developed, with epigastric pain and loss of 14 kg in weight. On admission to another hospital an abdominal mass was found, and the edge of the liver was felt 8 cm below the right costal margin. Laparotomy revealed a reticulum-cell sarcoma that involved the root of the mesentery; a biopsy of the liver was reported to be negative. Six weeks before entry cyclophosphamide, 150 mg daily, and prednisone, 60 mg daily, were instituted. The patient felt improved . . .
Abstract 262: Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models
Authors: Yingjuan June Lu, Leroy W. Wheeler, Vicky Cross, Elaine Westrick, Alex Lloyd, Christopher P. Leamon
Journal: Cancer Research (2016)

Abstract The PD-1/PD-L1 (programmed cell death protein 1; programmed death-ligand 1) pathway plays a key role in immunological tolerance and autoimmunity. PD-1 is primarily expressed on activated T and B cells while its receptor, PD-L1, is expressed in a variety of cell types including resting lymphocytes, DCs, and macrophages. Recently, multiple human solid tumor types (melanoma, NSCLC, RCC, ovarian, and colorectal cancer) have been found to overexpress PD-L1 within its tumor microenvironment. More importantly, PD-1/PD-L1 blocking agents (pembrolizumab, nivolumab, lambrolizumab, MPDL3280A) have been found active as a single agent or in combination with chemotherapy and some have produced durable clinical responses. On the other hand, human epithelial tumors are also known to overexpress the high-affinity folate receptor (FR)-alpha that is capable of bringing folate-linked drugs into the cell cytosol via endocytosis. Using flow cytometry, we assessed PD-L1 expression in various FR-positive syngeneic mouse tumor models (M109, Renca, L1210A, 4T1-Cl2, ID8-Cl15). PD-L1 expression was found to vary significantly among different tumor types and could be found not only on CD45- malignant cells but also on tumor stromal cells such as F4/80+CD11b+ tumor-associated macrophages. Using a rat anti-mouse PD-1 antibody (clone RMP1-14), we studied in-vivo efficacy of a folate-targeted chemotherapy in combination with PD-1/PD-L1 blockage in PD-L1-expressing tumor models. In syngeneic models with high PD-L1 expression and tumor-infiltrating lymphocytes, a synergistic and curable anti-tumor effect was observed and the animals developed tumor-protective immunity against rechallenge. Thus, our preliminary results suggest that folate-targeted chemotherapeutics may also be enhanced by PD-1/PD-L1 blockage by means of overcoming tumor-mediated immune suppression Citation Format: Yingjuan June Lu, Leroy W. Wheeler, Vicky Cross, Elaine Westrick, Alex Lloyd, Christopher P. Leamon. Combination therapy of folate-targeted chemotherapeutics with anti-PD-1 antibody against folate receptor-positive tumors in immunocompetent murine models. [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 262.
Infection Is the Major Cause of Mortality after Nonmyeloablative Unrelated Bone Marrow Transplantation with Alemtuzumab, Fludarabine and Melphalan.
Authors: Michael P. Carroll, Diane BuchBarker, Rowena Schwartz, Mounzer E. Agha, Cheryl Tompkins, Kristen Baileys, Kathleen O’Connell, Albert D. Donnenberg, Andrew M. Yeager
Journal: Blood (2004)
Abstract 410: Exhaustive scanning of mutation hotspot regions using a new tool: The MHS-ddPCR
Authors: Charles Decraene, Francois-Clement Bidard, Samia Belaabi, Etienne Rouleau, Adrien Saliou, Alexandre Houy, Maud Milder, Olivier Lantz, Marc Ychou, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon
Journal: Cancer Research (2016)

Abstract Background: Recent progress in the ‘liquid biopsy’ field in combination with the development of the droplet digital PCR (ddPCR) technology now enables non-invasive monitoring of cancer-related genomic alterations with high detection accuracy. Current ddPCR techniques represent the gold standard for the detection of point mutations that have been previously characterized on tumor tissues. However, ddPCR screen for only one mutation (or a few mutations, with multicolor ddPCR) per reaction. This is a clear limitation to use it as a discovery tool, to detect resistance-associated mutations that may appear during therapy (e.g. ESR1 activating mutations in breast cancer) or when tumor tissue is not available (e.g. EGFR activating mutations in lung cancers). Methods: We developed the Multiple Hotspot mutations detection by Single droplet digital PCR (MHS-ddPCR) method, a variant of the conventional ddPCR technique, which detects all genomic alterations within a hotspot region, using a unique couple of Taqman oligo-probes. We first established two specific assays covering KRAS and EGFR mutation hotspot regions, which are of clinical importance in the context of colorectal cancer. The assay for KRAS scans for the 7 most common mutations in codons 12 and 13 of the gene as well as all other mutations with lower frequency (&amp;lt;1%). The EGFR assay screens for all in-frame deletions of exon 19, which are frequent activating events in EGFR. Results: Sensitivity and specificity of MHS-ddPCR were assessed on decreasing fractions of tumor DNA mutated for KRAS. The KRAS assay reaches a sensitivity of 0.02% and was validated on plasma and tumor samples harboring a panel of different KRAS mutations. Similarly, the EGFR assay can detect numerous exon 19 deletions from patient samples and with limited amounts of tumor DNA. Conclusions: The MHS-ddPCR is extremely sensitive, works for numerous hotspot regions with different types of alterations (SNV, deletion) and is cost-effective as it combines multiple assays in one reaction. Citation Format: Charles Decraene, Francois-Clement Bidard, Samia Belaabi, Etienne Rouleau, Adrien Saliou, Alexandre Houy, Maud Milder, Olivier Lantz, Marc Ychou, Jean-Yves Pierga, Marc-Henri Stern, Charlotte Proudhon. Exhaustive scanning of mutation hotspot regions using a new tool: The MHS-ddPCR. [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 410.