tbuckley/cabot-search huggingface dataset:
Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function
Authors: Philipp S. Wild, Janine F. Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J.G. Leening, Uwe Völker, Vera Großmann, Jennifer A. Brody, Marguerite R. Irvin, Sanjiv J. Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V. Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero, Leo-Pekka Lyytikäinen, Daniel Tiller, J. Gustav Smith, Claire Monnereau, Marco R. Di Tullio, Solomon K. Musani, Alanna C. Morrison, Tune H. Pers, Michael Morley, Marcus E. Kleber, Jayashri Aragam, Emelia J. Benjamin, Joshua C. Bis, Egbert Bisping, Ulrich Broeckel, Susan Cheng, Jaap W. Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B. Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D. Hughes, Mika Kähönen, KNHI investigators, Jochen Kruppa, Karl J. Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J. Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M. Lindgren, Christina Loley, Calum A. MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P. Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M. Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P. Pramstaller, Olli T. Raitakari, Kenneth M. Rice, Fernando Rivadeneira, Jerome I. Rotter, Saku T. Ruohonen, Ralph L. Sacco, Tandaw E. Samdarshi, Helena Schmidt, Andrew S.P. Sharp, Denis C. Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H. Stricker, Praveen Surendran, Simon Thom, Anna M. Töglhofer, André G. Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P. Cappola, Joel N. Hirschhorn, Gary F. Mitchell, Nicholas L. Smith, Ervin R. Fox, Nicole D. Dueker, Vincent W.V. Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A. Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J. Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K. Arnett, Bruce M. Psaty, Stefan Blankenberg, Martin G. Larson, Stephan B. Felix, Oscar H. Franco, Tanja Zeller, Ramachandran S. Vasan, Marcus Dörr
Journal: Journal of Clinical Investigation (2017)

Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.
Temozolomide combined with radiation as first-line treatment in primary glioblastoma multiforme: Phase I/II-study
Authors: S. E. Combs, S. Gutwein, D. Schulz-Ertner, M. Van Kampen, C. Thilmann, M. M. Wannenmacher, J. Debus
Journal: Journal of Clinical Oncology (2004)

1531 Background: The role of chemotherapy in combination with radiation therapy is still discussed controversially in the treatment of primary glioblastoma multiforme. To evaluate the feasibility and toxicity of radiation and concomitant administration of temozolomide in patients with primary malignant glioma, this phase I/II study was conducted. Methods: 53 Patients with histologically confirmed WHO °IV malignant glioma were enrolled in the study. All patients were treated with radiation therapy with a total dose of 60Gy using conventional fractionation of 5x2.0Gy/week. Temozolomide was administered orally each therapy day at a dose of 50mg/m2. Results: Prior to radio-chemotherapy, complete resection of the tumor was performed in 14 patients, 22 patients received a subtotal resection, and in 17 patients only a biopsy could be performed. The median time interval between surgery and initiation of radio-chemotherapy was 21 days. Treatment related toxicity was very mild. Acute toxicity > °II was observed in one patient who developed °IV hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting which could be managed with odansetron medication. No severe late effects were observed. The median progression-free survival and the median overall survival were 8 months and 19 months, respectively. Actuarial overall survival was 72% at 1 year and 29% at 2 years. Age < 40 vs. > 40 and extent of surgery significantly influenced survival. Conclusion: The combination of temozolomide plus radiation therapy is feasible and safe by means of toxicity. Overall survival times were relatively high compared to the survival times reported for radiotherapy alone. By applying a dosage of 50mg/m2of temozolomide, application can be performed throughout the whole time course without interruption due to side effects and might contribute in a large manner to the prolonged overall survival. A clinical phase III trial is warranted to prove the superiority of combined radiotherapy with temozolomide compared to radiotherapy alone. No significant financial relationships to disclose.
Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline
Authors: Jadwiga A. Wedzicha, Marc Miravitlles, John R. Hurst, Peter M.A. Calverley, Richard K. Albert, Antonio Anzueto, Gerard J. Criner, Alberto Papi, Klaus F. Rabe, David Rigau, Pawel Sliwinski, Thomy Tonia, Jørgen Vestbo, Kevin C. Wilson, Jerry A. Krishnan
Journal: European Respiratory Journal (2017)

This document provides clinical recommendations for treatment of chronic obstructive pulmonary disease (COPD) exacerbations. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the Task Force's questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of COPD experts. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made: 1) a strong recommendation for noninvasive mechanical ventilation of patients with acute or acute-on-chronic respiratory failure; 2) conditional recommendations for oral corticosteroids in outpatients, oral rather than intravenous corticosteroids in hospitalised patients, antibiotic therapy, home-based management, and the initiation of pulmonary rehabilitation within 3 weeks after hospital discharge; and 3) a conditional recommendation against the initiation of pulmonary rehabilitation during hospitalisation. The Task Force provided recommendations related to corticosteroid therapy, antibiotic therapy, noninvasive mechanical ventilation, home-based management, and early pulmonary rehabilitation in patients having a COPD exacerbation. These recommendations should be reconsidered as new evidence becomes available.
Role of PAI-1 and TAFI in the mediation of fibrinolytic deficit in cancer patients
Authors: M. R. Florian-Kujawski, D. Hoppensteadt, O. Iqbal, M. Demir, M. Tobu, D. Fareed, J. Fareed
Journal: Journal of Clinical Oncology (2004)

9727 Background: Cancer associated thrombosis is known to have a multi-factorial pathogenesis involving up regulation of coagulation factors, down regulation of inhibitors and endothelial dysfunction. More recently, cancer patients have been shown to exhibit fibrinolytic deficit with impaired clot lysis. This has been mostly attributed to an increase in the circulating levels of plasminogen activator inhibitor 1 (PAI-1). Thrombin activatable fibrinolytic inhibitor (TAFI) has recently been identified as an additional mediator of fibrinolytic deficit that transforms fibrin to a plamsin resistant variant. Methods: To decipher the role of TAFI in this process, plasma samples obtained from 170 cancer patients with symptomatic thrombosis were analyzed for PAI-1, TAFI functional (F) and TAFI immunologic (I). An ELISA method was used for PAI-1 (Stago, Stamford, CT) and TAFI-I (American Diagnostic, Greenwich, CT), while a functional method was used for TAFI-F (Pentapharm, Ltd., Basel Switerland) Results: Baseline samples exhibited a marked increase in PAI-1 levels (140 ± 21) compared to normal (94 ± 14). The TAFI-I levels ranged from 56 –183 %NHP (123 ± 28 %NHP) which was higher than normal (85.1 ± 14 %NHP; n= 82). Interestingly, TAFI measured by functional levels were disproportionately lower (85 ± 26 %NHP) suggesting the consumption of this protease in cancer patients. In contrast to the TAFI I/F ratio approximately 1 for normal individuals, this ratio for cancer patients was 1.6 ± 0.1 (5.6 –0.7). When the PAI-1 levels were compared with F and I TAFI levels, no correlation was evident. This suggests independent regulation of these two proteins in cancer. The increased PAI-1 and TAFI-I levels were independent of the fibrinogen levels. Conclusions: The results clearly suggest that thrombotic complications in cancer patients may be partly due to the fibrinolytic deficit, which is modulated by an up regulation of both PAI-1 and TAFI. Furthermore, the two regulators of fibrinolysis mediate their effects independently. Since the TAFI-I levels are disproportionately high, this enzyme may complex with endogenous proteins modulating its functionality. No significant financial relationships to disclose.
Randomized phase II-III study of matrix metalloproteinase inhibitor (MMPI) BMS-275291 in combination with paclitaxel (P) and carboplatin (C) in advanced non-small cell lung cancer (NSCLC): NCIC-CTG BR.18
Authors: N. B. Leighl, F. Shepherd, L. Paz-Ares, J.-Y. Douillard, C. Peschel, A. Arnold, D. Tu, S. Galbraith, K. Hann, L. Seymour
Journal: Journal of Clinical Oncology (2004)

7038 Background: BMS- 275291 is a broad spectrum MMPI that was not associated with the dose-limiting joint toxicity seen with other MMPIs in phase I studies. Methods: Chemotherapy-naive patients with Stage IIIB/IV NSCLC, performance status (PS) 0–2 and adequate organ function were eligible. All patients received P (225 mg/m2) + C (AUC 6) IV q21d (max 8 cycles), and were randomized (double-blind) to receive BMS-275291, 1200 mg PO daily or placebo until disease progression. The primary study endpoint was survival (OS); secondary endpoints included progression-free survival (PFS), response rates (RR), toxicity, and quality of life (QoL). Results: From 2000 to 2002, 774 pts were randomized from 76 centres in North America and Europe (planned accrual 750 in 26 m). Pretreatment characteristics were well balanced between arms: median age 61; male 73%; stage IV 79%; PS 0/1 88%. 614 deaths have occurred, with median follow-up of 18 mos. Interim analysis revealed no survival advantage and increased toxicity in the experimental arm, and study treatment was stopped. Median OS in the final analysis was 8.6 mos in the BMS-275291 arm, 9.2 mos in the control arm (p=0.3). Median PFS and RR were 4.9 mos, 25.8% in the BMS 275291 arm, and 5.3 mos, 33.7% in the control arm. Toxicity was significantly higher in the BMS-275291 arm vs control: flu-like symptoms 8.1% v 4.5%; hypersensitivity reactions 8.6% vs. 2.4%; febrile neutropenia 9.7% vs. 5.5%; rash 12.2% vs. 0.8%; treatment stopped for toxicity 33.3% vs 23.5%. QoL scores during chemotherapy were similar in both arms, with deterioration in the experimental arm post-chemotherapy. Conclusions: BMS-275291 added to chemotherapy increases toxicity and does not improve survival in advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Educational program for medical residents in cancer pain management.
Authors: Shyam Ravisankar, Ela Eris, Alice Joy Cohen
Journal: Journal of Clinical Oncology (2017)

198 Background: Studies have shown significant deficits in the knowledge of physicians in Cancer Pain Management (CPM). We implemented an educational program on CPM for medical residents with pre and post-testing to assess baseline knowledge and the improvement after education. Methods: The content of the lecture was derived from the Cancer Pain Education Resource (CAPER). It included assessment, non-pharmacological interventions, equi-analgesic conversions , titration, side effects, withdrawal, dependence and addiction. An online questionnaire was created to assess the baseline knowledge and the residents accessed it using their mobile phones. After the lecture the same was used to assess the improvement in knowledge. 22 residents from Newark Beth Israel Internal Medicine Residency Program participated in the lecture and the pre/post-tests. After the lecture, they were given a pocket card with opioid equi-analgesic dosing calculations.Two months later, the same questionnaire was used to assess the retained knowledge. Results: The pretest score was 71% and after the lecture it improved to 81%. After 2 months the score was 72%. Notably, the knowledge of equi-analgesic conversions had increased. 95 % of the residents were very satisfied with the lecture and wanted more education on CPM. Improvement in knowledge on specifics of CPM are shown in Table. Conclusions: One of the ways to improve CPM is to focus on education of residents. After a single lecture, there was improvement in all areas of deficiency.The use of simple tools like pocket cards can help to improve knowledge. Our plan is to expand this program to medical students and have additional lectures. We believe that these lectures will improve the quality of CPM in patients. [Table: see text]
Pharmacokinetics and tolerability of doxorubicin in newly diagnosed lymphoma patients with hepatic impairment.
Authors: Catherine Lai, Diane Cole, Margaret Shovlin, Brigitte C. Widemann, Kieron Dunleavy, Wyndham Hopkins Wilson
Journal: Journal of Clinical Oncology (2014)

8547 Background: Doxorubicin (dox) is critical for the curative treatment of DLBCL. Principally metabolized in the liver, early studies showed significantly decreased clearance (cl) in patients (pts) with hepatic impairment, leading to empiric dox reduction in pts with elevated bilirubin. No studies have analyzed dox pharmacokinetics (pk) and clinical toxicity in lymphoma pts with hepatic impairment. Methods: Pts with newly diagnosed aggressive lymphoma received 6 to 8 cycles of DA-EPOCH +/-R at the NCI. Of 70 pts studied, 61 had normal and 9 had elevated bilirubin (> 1.2mg/dL). All pts received full dose dox (40 mg/m2) over 96-hours on cycle 1. Blood samples were collected for dox and doxorubicinol (doxor) pk at 0, 22 and 96 hours after infusion began. Results: The median (range) dox cl in pts with elevated versus normal bilirubin was 393ml/min/m2 (294-610) vs. 630 ml/min/m2(262-1596) (p= 0.0036). Median (range) plasma dox steady state concentrations (Css) at 96 hours were 0.031 (0.020-0.042) vs. 0.021 (<LLQ-0.045) μM (p=0.0036) and doxor Css were 0.025 (0.008–0.052) vs. 0.010 (<LLQ–0.021)µM (p=0.0028) in elevated versus normal bilirubin. Neutropenia was lower and thrombocytopenia (tcp) was higher in pts with elevated bilirubin (see table below). Response rates (RR) were similar: Complete response (CR) was achieved in 78% (7/9) versus 82% (50/61) and PR in 0% (0/9) vs 7% (4/61) of pts with elevated vs normal bilirubin. Conclusions: Pts with elevated bilirubin had reduced cl of dox, but was within the range of normal. Importantly, there were no differences in febrile neutropenia - tcp was higher in pts with elevated bilirubin but was not clinically meaningful. RR were similar between the 2 groups. Our results do not support the empiric dose reduction of dox in pts with aggressive lymphomas receiving potentially curative treatment. Characteristics Elevated bilirubin Normal bilirubin Median age (yrs) 44 (24-62) 46 (21-75) IPI (int hi/hi risk) 67% (6/9) 28% (17/61) ANC nadir < 500/mm3 (% pts C1) 33% (3/9) 52% (32/61) TCP nadir < 25x103/mm3 (% pts C1) 89% (8/9) 0% (0/61) Febrile neutropenia (% pts C1) 22% (2/9) 16% (10/61) G3/4 GI and neuro tox (% pts C1) 33% (3/9) 11% (7/61)
Study of the regulation of the G2/M checkpoint in acute myeloid leukemia cell lines
Authors: Christine Didier, Muriel Quaranta, Cindy Cavelier, Cecile Demur, Stephane Manenti, Bernard Ducommun
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4362 

Acute myelocytic leukemia (AML) cells exposed to genotoxic agents arrest their cell cycle at the G2/M checkpoint and are naturally chemoresistant. To gain insight in the understanding of this resistance, we compared the ability of immature CD34+ versus mature CD34- AML cell lines (KG1a and U937 respectively) to bypass a DNA damage cell cycle checkpoint in G2. Here, we report evidence for a more stringent control of G2/M checkpoint in KG1a than in U937 cells. We show that in both cell types the CDC25B phosphatase and the PLK1 kinase participate to the G2/M checkpoint recovery. We also show that inhibition of CHK1 by UCN-01 in immature KG1a cells allows checkpoint exit and sensibilisation to genotoxic agent. Finally, UCN-01 potentialises genotoxic-induced inhibition of plating efficiency of AML blasts from patients.

Together our results demonstrate that checkpoint stringency varies during maturation process and indicate that targeting checkpoint mechanisms might represent an attractive therapeutic opportunity for chemoresistant immature AML.
A quality improvement initiative to reduce low-value red blood cell transfusions in hospitalized oncology patients.
Authors: Tiffany Wong, Perry Harris Dubin, Michael Davenport, Geoffrey D Bass, Jennifer Myers, Jason Wagner
Journal: Journal of Clinical Oncology (2017)

116 Background: Red blood cell (RBC) transfusions are costly, a limited resource, and pose serious medical risk. While most disciplines now transfuse sparingly, hospitalized oncology patients at our institution are often transfused liberally. We conducted a QI initiative to reduce practice variation by adopting a standardized restrictive transfusion strategy. Methods: We performed a retrospective analysis of the total number of pre-transfusion hemoglobin-adjusted RBC transfusions from 02/2015 to 08/2015. Patients with severe gastrointestinal bleeding and acute coronary syndrome were excluded. Extensive feedback from providers was solicited and a comprehensive review of the evidence was performed to understand the process driving existing practices. This information and a root cause analysis were presented to key members of Oncology leadership to gain consensus on a RBC transfusion algorithm. The final algorithm recommended transfusing to a Hg goal of 8 g/dL if the platelet count was ≤ 50K; otherwise the Hg goal was 7 g/dL. We defined low-value RBC transfusions as a transfusion occurring outside the parameters of this algorithm. A multifaceted educational campaign comprising in-person meetings and web-based postings was launched to target ward nurses, advanced practitioners, residents, and attending physicians. RBC transfusions were then tracked to monitor adherence to the algorithm. Results: Analysis of the current process using QI methods found that RBC transfusion practices are most influenced by uncertainty of best practice and variation in attending preference. After the implementation of a RBC transfusion algorithm, the overall number of low-value RBC transfusions decreased from 29.6% to 19.7% (p &lt; 0.001). This reduction was most marked in patients with platelet counts &gt; 50K where there was a reduction from 78.7% to 55.6% (p &lt; 0.001). A 9.9% overall reduction corresponds to roughly 520 fewer RBC transfusions per year, which suggests an annual estimated cost savings of $520,000. Conclusions: By using a standardized QI framework, we were able to successfully decrease variation in practice that results in low-value RBC transfusions in hospitalized oncology patients.
Use of PTEN status to determine the functional outcome of combined MEK and mTOR inhibition.
Authors: Ludovica Ciuffreda, Italia Falcone, Ursula Cesta Incani, Giovanni Sette, Adriana Eramo, Anais Del Curatolo, Ruggero De Maria, Francesco Cognetti, Michele Milella
Journal: Journal of Clinical Oncology (2012)

e13512 Background: PTEN is a lipid phosphatase couteracting the activity of the PI3K pathway. PTEN mutations and deficiencies are prevalent in many types of human cancers and are associated with poor prognosis and therapeutic resistance. MAPK is another key cellular network that works independently from, in parallel to, and/or through interconnections with PI3K to promote cancer development. Here we investigated whether a strategy combining MEK and mTOR inhibition may be effective in preclinical models of human cancer and the role of PTEN loss in determining sensivity/resistance to single and combined pathway inhibition. Methods: We employed in vitro assays (cell proliferation assays, cell cycle and apoptosis analysis, WB, and ELISA assays) to determine functional and molecular drug effects. Pharmacologic interactions between MEK and mTOR inhibitors were analyzed by conservative isobologram analysis using a fixed dose-ratio experimental design. Results: In cell lines with wt-PTEN (including melanoma, breast, lung, and colon cancer), combined MEK and mTOR blockade achieves synergistic effects at suboptimal drug concentrations but becomes frankly antagonistic in the presence of complete inhibition of MEK-to-ERK signaling (combination index - CI: 1.2-&gt;1000). This, in turn, led to the identification of a novel crosstalk mechanism by which MEK blockade restores PTEN expression and cross-inhibits the PI3K/AKT/mTOR pathway, thus bypassing the need for double pathway blockade. Conversely, in cancer cell lines with PTEN loss, combined MEK and mTOR blockade resulted in strongly synergistic effects (CI: 0.0005-0.4), due to cooperative induction of apoptosis. A similar synergistic growth inhibition was also observed in a patient-derived lung cancer stem cell line, which displayed low to undetectable PTEN protein levels. Conclusions: Our results suggest that combined MEK and mTOR inhibition exerts strongly synergistic effects in cancer models with PTEN loss. This notion may be helpful in selecting appropriate cellular (and possibly clinical) contexts for the design rational therapeutic strategies based on concomitant inhibition of the RAF/MEK/ERK and PI3K/AKT/mTOR pathways.