tbuckley/cabot-search huggingface dataset:
Phase III open label randomized controlled trial comparing intravenous iron sucrose to oral ferrous sulphate (without erythropoiesis stimulating agents) in the treatment of cancer related iron deficiency anemia.
Authors: Vanita Noronha, Vijay Maruti Patil, Amit Joshi, Sucheta More, Supriya Goud, Sachin Punatar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2016)

10136 Background: In patients with malignancy and iron deficiency (actual or functional) anemia not receiving erythropoiesis stimulating agents (ESA), the optimal mode of iron supplementation is unknown. Methods: Adult patients with malignancy requiring chemotherapy, hemoglobin (Hb) < 12 g/dl and at least 1 feature indicating iron deficiency: serum ferritin < 100 mcg/ml, transferrin saturation < 20% or hypochromic red blood cells > 10% were randomized to IV iron sucrose (dose calculated from formula for total iron deficit, administered in 2 doses 3 weeks apart with each chemotherapy cycle) or to oral ferrous sulphate 100mg three times a day for 42 days. The primary endpoint was the change in Hb from baseline to 6 weeks. Secondary endpoints included blood transfusion, QOL, toxicity, response rate and overall survival. Results: 192 patients were enrolled over 5 years. The median age was 51 years. Over 95% patients had solid tumors; intent of therapy was curative in 66%. 78% patients were compliant with therapy in each arm. The mean absolute increase in Hb at 6 weeks was 0.11 g/dl (standard deviation [SD]:1.48) in the IV arm and -0.16 g/dl (SD:1.36) in the oral arm, p = 0.23. 19% (14 out of 74; 95% CI-11.5%-29.5%) of patients on IV iron and 12% (9 out of 75; 95%CI-6.3%-21.6%) of patients on oral iron had a rise in Hb of 1.5 g/dl at 6 weeks, p = 0.27. 12 patients in each arm required blood transfusion. Gastrointestinal toxicity (any grade) developed in 41% patients on IV iron and 44% patients on oral iron, p = 1.0. Hypersensitivity developed in 5 patients on IV iron, and none on oral iron, p = 0.059. There was no difference in the response to therapy or overall survival in either arm; p = 0.73. Multivariate analysis revealed that mode of administration of iron, age, gender, intent of therapy and baseline Hb did not significantly impact response to iron therapy. QOL analysis will be presented. Conclusions: Oral iron was similar to IV iron in patients with malignancy and iron deficiency anemia with no difference in the need for blood transfusions, toxicity or outcome measures. IV iron led to numerically more hypersensitivity reactions. Clinical trial information: CTRI/2016/01/006520.
Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis
Authors: Anthony C. Gordon, Gavin D. Perkins, Mervyn Singer, Daniel F. McAuley, Robert M.L. Orme, Shalini Santhakumaran, Alexina J. Mason, Mary Cross, Farah Al-Beidh, Janis Best-Lane, David Brealey, Christopher L. Nutt, James J. McNamee, Henrik Reschreiter, Andrew Breen, Kathleen D. Liu, Deborah Ashby
Journal: New England Journal of Medicine (2016)

Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis.
Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice
Authors: Liang Wei, Brian J. Leibowitz, Xinwei Wang, Michael Epperly, Joel Greenberger, Lin Zhang, Jian Yu
Journal: Journal of Clinical Investigation (2016)

Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration. PD treatment also enhanced LGR5+ stem cell survival and regeneration after radiation. PD was an on-target inhibitor of RB phosphorylation and blocked G1/S transition in the intestinal crypts. PD treatment strongly but reversibly inhibited radiation-induced p53 activation, which blocked p53-upregulated modulator of apoptosis-dependent (PUMA-dependent) apoptosis without affecting p21-dependent suppression of DNA damage accumulation, with a repair bias toward nonhomologous end joining. Further, deletion of PUMA synergized with PD treatment for even greater intestinal radioprotection. Our results demonstrate that the cell cycle critically regulates the DNA damage response and survival of intestinal stem cells and support the concept that pharmacological quiescence is a potentially highly effective and selective strategy for intestinal radioprotection.
Imatinib plus hydroxyurea in pretreated non-progressive glioblastoma (GBM)—A single center phase II study
Authors: G. Dresemann, C. Hosius, Z. Nikolova, L. Letvak
Journal: Journal of Clinical Oncology (2006)

1583 Background: GBM is a highly malignant tumor with a median survival of less than 15 months. Dysregulated signalling of platelet derived growth factor receptors (PDGF-Rs) is implicated in pathogenesis. Imatinib (I) plus Hydroxyurea (HU) is effective in patients (pts) with recurrent progressing GBM. In a pilot series of 30 pts with recurrent GBM progression free survival (PFS) at 6 and 24 months was 32 % and 16 % respectively. 37 % of pts achieved disease stabilisation (SD). Despite the aggressive course of GBM, short periods without progression after primary treatment or effective treatment of relapse is common. The current Phase II study is designed to analyse the efficacy of I plus HU treatment in GBM pts with SD as sequential treatment. Methods: From Dec 2003 up to June 2005 30 pts were included. No enzyme-inducing anticonvulsive drugs were allowed. I at the dose of 600 mg and 1000 mg of HU were given as a continuous daily treatment, follow up included blood cell count weekly and magnetic resonance imaging (MRI) every 6 weeks. The primary endpoint is 12 months PFS. Results: All pts are eligible for safety and 28 pts of them for 6 months PFS and 6 months overall survival (OS) so far; 25 pts were male, 5 pts female, median age was 44 years (32 to 71). All 30 pts had prior irradiation, 21 pts had temozolomid containing and 9 pts non-temozolomid containing regimens. Eight pts were free from relapse, 17 pts after first and 5 pts after second relapse. 25 pts had measurable disease in MRI scan, 5 pts had no evidance of disease. The median follow up was 14 months. The best response was partial remission in 4 pts. SD for more than 3 months in 20 pts. 6 months PFS was 64% (18/28) and 6 months OS was 93 % (26/28). Hematotoxicity grade 2 and 3 occurred in 11 out of 30 pts (anemia grade 3: 2 pt; anemia grade 2: 4 pts; leucopenia grade 3:2 pts; grade 2: 7 pts; thrombopenia grade 2: 4 pts) and required dose reduction of HU in 8 pts, dose reduction of I in 1 patient and G-CSF subcutaniously in 8 pts. Conclusions: I (600 mg/d) and HU (1000 mg/d) showed significant efficacy as sequential treatment. Hematotoxicity was higher compared to I (400 mg/d) and HU (1000mg/d). Six months PFS and OS data are promising so far. Complete analysis according to the primary endpoint will be presented at the 2006 ASCO meeting. [Table: see text]
Transcatheter Aortic Valve Replacement to Treat Pure Aortic Regurgitation on Noncalcified Native Valves
Authors: Marina Urena, Dominique Himbert, Patrick Ohlmann, Giuliana Capretti, Coppelia Goublaire, Michel Kindo, Olivier Morel, Walid Ghodbane, Bernard Iung, Alec Vahanian
Journal: Journal of the American College of Cardiology (2016)
A phase II trial of saracatinib (AZD0530), an oral Src inhibitor, in previously treated metastatic pancreatic cancer.
Authors: W. A. Messersmith, S. Nallapareddy, J. Arcaroli, A. Tan, N. R. Foster, J. J. Wright, J. Picus, B. C. Goh, M. Hidalgo, C. Erlichman
Journal: Journal of Clinical Oncology (2010)

e14515 Background: Src family tyrosine kinases are overexpressed in pancreatic cancers, and the oral Src inhibitor saracatinib (AZD0530) has shown antitumor activity in a preclinical PancXenoBank human tumor explant model in nude mice (Rajeshkumar et al, Clin Can Res 2009). We conducted a CTEP-sponsored phase II clinical trial of saracatinib as monotherapy in previously treated metastatic pancreas cancer patients (pts), with a primary endpoint of 6-month survival. Methods: A two-stage phase II design was used. Pancreatic cancer pts (ECOG PS 0-1) who progressed on prior gemcitabine regimens were enrolled. Saracatinib (175 mg/day) was administered daily orally for 28-day cycles. Secondary end points included toxicity, response (RECIST), overall survival, time to progression, and exploration of pharmacodynamic effects in biopsiable pts. Results: Of 19 pts enrolled, 18 patients were evaluable: median age 62 (range 34-78), 10F/8M, all previously treated with gemcitabine. Median of one cycle was administered (range: 1 to 4). Only 1 grade 3/4 adverse event occurred in > 1 patient, g 3 fatigue (2 pts). Only 2 pts survived for at least 6 months (11%), which did not meet the 18% criteria for continuation to stage II.Median survival was 2.5 months and median time to progression was 1.6 months.No objective responses were seen. BAseline biopsies from three patients were analyzed with RT-PCR for K-top scoring pairs(K-TSP) predictor from preclinical model:all 3 predicted resistant and di not survive 6 months. Conclusions: In an unselected population of previously treated advanced pancreatic cancer pts, saracatinib failed to improve 6-month survival compared to a historical database. Sarcatinib was well tolerated in the above treated population. A pharmacodiagnostic (PDx) pre-selection strategy based on the kTSP predictor from the PancXenoBank will be employed to enrich for patients most likely to benefit in a tandem two-step phase II design. This approach will also test the hypothesis that PDx from a human explant model will enrich for patients most likely to benefit. Supported by NCI/CTEP (Protocol #7602), N01-CM62205 (PI, Erlichman), 1R21CA135622-01 (PI, Messersmith). No significant financial relationships to disclose.
冠動脈疾患患者におけるポイントオブケア検査(VerifyNow-P2Y12)によって評価された血小板反応性に対するCYP2C19多型の影響
Authors: Tohma Yuichiro, Sakai Koyu, Noguchi Masahiko, Enomoto Soichiro, Sato Koji, Katoh Masashi, Yokoi Hiroyoshi, Iwabuchi Masashi, Nosaka Hideyuki, Nobuyoshi Masakiyo
Journal: Circulation (2011)
The extracellular matrix deposited by asthmatic airway smooth muscle cells in a resting state reflects a healthy matrix
Authors: Louise Harkness, Anthony Ashton, Janette Burgess
Journal: European Respiratory Journal (2015)

Introduction: The remodelled asthmatic airway features an altered extracellular matrix (ECM) & increased vasculature. Previous studies found asthmatic (A) airway smooth muscle cells (ASMCs) to deposit an ECM with enhanced bioactivity. These studies however investigated ECM deposited in the presence of proliferative stimuli. Objective: This study examined the regulatory activity of the ECM generated by A & non-asthmatic (NA) ASMCs under quiescent conditions. Methods: ECM from primary human NA& AASMCs was isolated under quiescent conditions. NA-, AASMCs, or human umbilical vein endothelial cells (HUVECs) were seeded onto decellularised NA-or AASM-ECM. Metabolic activity was measured by MTT. ASMC proliferation (CyQUANT), HUVEC attachment & transwell migration (toluidine blue) were also quantified. Results: NAASMCs proliferated less on A-ECM compared to NA-ECM (N=3&5 P=0.04) but there were no differences in metabolic activity on NAor A-ECMs (N=4&3 P=0.21). AASMCs had no difference in proliferation or metabolic activity on A-ECM (N=3&5) versus the NA-ECM (N=4 for both P=0.44&0.28). HUVECs showed similar attachment to NA& A-ECMs (N=10&8 P=0.97). HUVEC metabolic activity on & migration through the quiescent ECM was not different between A-& NA-ECM (N=10&11 P=0.83, and N=3&5 P=0.30). Conclusion: A-ECM produced under quiescent conditions has similar bioactive properties to NA-derived ECM. This study contrasts reports of an altered ECM bioactivity generated by AASMCs under stimulated conditions. These data provide further evidence for maintaining AASMCs in a resting state to prevent deposition of an abnormal ECM which may contribute to the remodelling in the airways.
Excess treatment related deaths and impaired quality of life show raltitrexed is inferior to infusional 5FU regimens in the palliative chemotherapy of advanced colorectal cancer (CRC): Final results of MRC CR06
Authors: T Maughan, R James, D Kerr, J Ledermann, C McArdle, M Seymour, C Johnston, R Stephens
Journal: Annals of Oncology (2000)
Viral mimic poly-(I:C) attenuates airway epithelial T-cell suppressive capacity: implications for asthma
Authors: Jürgen Schwarze, Paul M. Fitch, Janneke Heimweg, Claire Errington, Reina Matsuda, Harold G. de Bruin, Maarten van den Berge, Antoon J.M. van Oosterhout, Irene H. Heijink
Journal: European Respiratory Journal (2016)

In allergen-sensitised asthmatic individuals, allergen-specific type-2 T-helper cells proliferate and secrete type-2 cytokines ( e.g. interleukin (IL)-4, -5 and -13), driving the airway inflammatory response that gives rise to the clinical symptoms of asthma. Both early-life sensitisation to aeroallergens and lower respiratory viral infections are important environmental risk factors for developing asthma. Additionally, respiratory viral infections are the most common trigger for asthma exacerbations. Of interest, many asthma susceptibility genes are expressed in the airway epithelium [1], which forms the first continuous line of defence against inhaled environmental insults, including viruses and aeroallergens. Impaired immune regulation and failure to maintain tolerance to allergens is thought to contribute to allergic sensitisation. Asthma epithelium may be deficient in its innate immune defence against viral infections, resulting in increased viral replication upon rhinovirus infection compared to nonasthma-derived epithelial cultures [2]. Furthermore, there is evidence for loss of the mucosal immune barrier in asthma, with disruption of epithelial integrity [1, 3]. This may lead not only to increased permeability, but also to the release of pro-inflammatory mediators, specifically of cytokines that drive type-2 responses [3, 4]. We recently observed that the ability of allergens to disrupt epithelial barrier function is related to the development of type-2-mediated inflammation in asthma [5, 6]. Furthermore, we demonstrated that healthy murine lung epithelium is a potent inhibitor of T-cell proliferation and that this inhibition is lost upon viral infection [7]. It is unknown if this immune regulatory effect is displayed by human epithelium and is dysregulated in asthma. We hypothesise that changes in this regulatory effect translate into aberrant regulation of T-cell responses in asthma. We studied the epithelial regulation of T-cell proliferation and cytokine responses upon epithelial stimulation with a viral mimic, using co-culture of human T-cells and primary bronchial epithelial cells (PBECs) from healthy controls and asthma patients. Airway epithelial regulation of T-cell activity may be impaired during virus-induced exacerbations in asthma <http://ow.ly/b9KB303KVul>
Cost of non-small cell lung cancer in Italy. Results of the longitudinal study ALCEA (Advanced Lung Cancer Economic Assessment)
Authors: F. Perrone, G. Benelli, S. Lopatriello, L. Portalone, F. Salvati, P. Zorat, C. Negrini
Journal: Journal of Clinical Oncology (2004)

8265 Background: Lung cancer is extremely common and its cost for society is not extensively studied. ALCEA (Advanced Lung Cancer Economic Assessment) -an observational cost-of-illness study -has generated economic data on patients affected by NSCLC in an advanced stage, exploring both direct and indirect costs determined by this pathology in Italy. Methods: A total of 189 patients treated with first line chemotherapy (1st L), second line chemotherapy (2nd L) or supportive therapy (ST) were observed for a six-month period or until death. Direct costs were measured according to consumption of healthcare resources (hospitalisations, specialist visits, drugs, diagnostic tests and laboratory tests) and costed according to current Italian tariffs. A sample of total costs and an average per patient cost were produced and analysed for the 1st L, 2nd L and supportive therapy. Indirect costs were evaluated only in terms of reduced or lost productivity due to morbidity or mortality of patients. Results: In 1st and 2nd line treatments the highest direct costs were determined by hospitalisations due to chemotherapy -with a mean cost per patient of € 4,350 and € 2,417 respectively - and by hospitalisations due to adverse eventsother disease related reasons–€ 3,819 and € 5,108 respectively. For ST the highest costs were generated by hospitalisations occurred for reasons other than chemotherapy with a mean per patient cost of € 6,211. The productivity loss was estimated to be a total of 369 years, which means about €11,390,000 and an average per patient cost of € 60,263. Conclusions: ST may be a suggested strategy in the treatment of advanced NSCLC when chemotherapy appears to have a limited efficacy and worsening of patient performance status. The management of NSCLC imposes a considerable burden on society. Infact, it implies a high level of utilization of healthcare resources and a significant productivity loss, despite many patients have already retired at the time of first diagnosis. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Abstract 3897: High-throughput profiling of actionable mutations in salivary duct carcinoma
Authors: Bo Mi Ku, Yeon-Hee Bae, Hyun Ae Jung, Jong-Mu Sun, Young Hyeh Ko, Han-Sin Jeong, Young-Ik Son, Chung-Hwan Baek, Keunchil Park, Myung-Ju Ahn
Journal: Cancer Research (2015)

Abstract Salivary duct carcinoma (SDC) is a highly aggressive subtype of salivary gland cancers and there is no established standard therapy for this disease. Thus, development of molecular markers for SDC will be important to guide the diagnosis and therapy of this aggressive tumor. We performed next-generation sequencing using the Ion Torrent AmpliSeq cancer panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes, and we analyzed copy number variations (CNVs) of 21 genes by NanoString nCounter for 37 patients with SDC. Fluorescent in situ hybridization was also conducted to confirm ERBB2 gene amplification. Clinical records and tumor histopathology of the patients were retrospectively reviewed. Genetic alterations were detected in 29 of 37 (78.3%) tumors, including mutations in PIK3CA (N = 9, 24.3%), ERBB2 (N = 4, 10.8%), and EGFR (N = 4, 10.8%). To our knowledge, this is the first time that ERBB2 mutations have been reported in this tumor type. Both PIK3CA and ERBB2 mutation status were associated with poor overall survival, but without statistical significance. ERBB2 amplification was strong and common in SDC and almost all cases also exhibited EGFR and ERBB3 amplifications. This study reports the largest and most comprehensive analysis of DNA aberrations in SDC. Our results show that PIK3CA and/or ERBB2 alterations in the development of SDC might be a useful diagnostic tool and could serve as a potential therapeutic target. Key words: Salivary duct carcinoma, next-generation sequencing, molecular markers, PIK3CA, ERBB2, EGFR Citation Format: Bo Mi Ku, Yeon-Hee Bae, Hyun Ae Jung, Jong-Mu Sun, Young Hyeh Ko, Han-Sin Jeong, Young-Ik Son, Chung-Hwan Baek, Keunchil Park, Myung-Ju Ahn. High-throughput profiling of actionable mutations in salivary duct carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3897. doi:10.1158/1538-7445.AM2015-3897
Emerging Issues and Opportunities in Health Information Technology
Authors: Elizabeth A. Nardi, Lisa Korin Lentz, Katherine Winckworth-Prejsnar, Amy P. Abernethy, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2016)

When used effectively, health information technology (HIT) can transform clinical care and contribute to new research discoveries. Despite advances in HIT and increased electronic health record adoption, many challenges to optimal use, interoperability, and data sharing exist. Data standardization across systems is limited, and scanned medical note documents result in unstructured data that make reporting on quality measures for reimbursement burdensome. Different policies and initiatives, including the Health Information Technology for Economic and Clinical Health Act, the Medicare Access and CHIP Reauthorization Act, and the National Cancer Moonshot initiative, among others, all recognize the impact that HIT can have on cancer care. Given the growing role HIT plays in health care, it is vital to have effective and efficient HIT systems that can exchange information, collect credible data that is analyzable at the point of care, and improves the patient-provider relationship. In June 2016, NCCN hosted the Emerging Issues and Opportunities in Health Information Technology Policy Summit. The summit addressed challenges, issues, and opportunities in HIT as they relate to cancer care. Keynote presentations and panelists discussed moving beyond Meaningful Use, HIT readiness to support and report on quality care, the role of HIT in precision medicine, the role of HIT in the National Cancer Moonshot initiative, and leveraging HIT to improve quality of clinical care.
Obesity, a worldwide epidemic related to heart disease and stroke: Group II: Age-dependent risk factors for obesity and comorbidities
Authors: S. T. St Jeor, L. L. Hayman, S. R. Daniels, M. W. Gillman, G. Howard, C. M. Law, C. E. Lewis, E. Poehlman
Journal: Circulation (2004)

Dynamic processes that occur over the life span determine the development of obesity and associated chronic diseases. Perturbations, or “insults,” that determine excessive weight gain leading to obesity may occur anytime from before conception to embryonic, fetal, infant, childhood, adolescent, and adult life. These insults can affect both somatic growth and the maturation of metabolic systems and may include a range of determinants, including societal, lifestyle, biological, and genetic factors that often act in concert with one another. A life-course approach to chronic disease (Figure 1) classifies determinants in several different ways.1 A critical period refers to a specific period of development when an insult has lasting effects on the structure or function of organs, tissues, and body systems. When the insult is not completely deterministic, these periods may be referred to as sensitive rather than critical. Effects during critical periods may act alone or be modified by later insults. Alternatively, some insults may act at any period of development; they may accumulate over time independently or be correlated through clustering. These models are useful in helping determine which early life factors are important in the assessment of later disease. Although age-dependent risk factors may vary worldwide, identification of common critical or sensitive periods and plausible determinants will help improve overall treatment and prevention of obesity over the life span.
“Get the Consent”—Nonfinancial Conflict of Interest in Academic Clinical Research
Authors: Abby R. Rosenberg
Journal: Journal of Clinical Oncology (2016)

During a presentation at the 2016 ASCO Annual Meeting in Chicago, Illinois, a bioethicist joked that financial conflict of interest (COI) disclosures were the great success of modern bioethics. 1I appreciated the irony; perhaps our focus on financial COI has overshadowed other competing interests at the intersection of academic medicine and clinical research.Nonfinancial COIs may be equally pervasive, are often unavoidable, and are no less important.