tbuckley/cabot-search huggingface dataset:
Saturable pharmacokinetics and paclitaxel pharmacodynamics in children with solid tumors.
Authors: D S Sonnichsen, C A Hurwitz, C B Pratt, J J Shuster, M V Relling
Journal: Journal of Clinical Oncology (1994)

PURPOSE Our aim was to evaluate the pharmacokinetics and pharmacodynamics of paclitaxel (Taxol; Bristol-Myers Squibb Co, Princeton, NJ) in children, and to determine whether paclitaxel exhibited saturable pharmacokinetics. PATIENTS AND METHODS We evaluated the pharmacokinetics and pharmacodynamics of paclitaxel (200 to 420 mg/m2) administered as a 24-hour intravenous (i.v.) infusion in a phase 1 study of 30 pediatric patients (age, 2.3 to 22.8 years) with refractory solid tumors. Fourteen serial blood samples were obtained during and up to 48 hours after the infusion, and paclitaxel concentrations were measured by a high-performance liquid chromatography-UV (HPLC-UV) method. Four pharmacokinetic models were compared for their ability to describe the patients' data. RESULTS Paclitaxel disposition was not consistent with a first-order, two-compartment pharmacokinetic model. Rather, the majority of data sets were best described by a two-compartment model that incorporated both saturable tissue distribution and saturable elimination; a smaller number of patient data sets were best described by models that incorporated either saturable distribution or saturable elimination. Clearance was dose-dependent, with a median clearance at the lower dosages (&lt; 400 mg/m2) of 161 mL/min/m2, and at the highest dosages (&gt; 400 mg/m2) of 123 mL/min/m2 (P = .044). The duration that paclitaxel plasma concentrations exceeded 0.1 mumol/L was highly variable (range, 26 to 71 hours). There was a trend toward higher median area under the concentration-versus-time curve (AUC) in those children with musculoskeletal (72 mumol/L.h; P = .054) or neurologic toxicity (54 mumol/L.h; P = .062) versus those without toxicity (30 mumol/L.h). Toxicity was not significantly correlated with dosage. CONCLUSION We conclude that paclitaxel distribution and elimination are saturable, and that estimates of paclitaxel systemic exposure correlate better with toxicity than does dosage.
Abstract 17767: A MiR-31-dependent Loss of Dystrophin &amp; Nnos in the Human Atria Plays a Key Role in Atrial Fibrillation-induced Electrical Remodelling
Authors: Svetlana Reilly, Xing Liu, Ricardo Carnicer, Timothy Rajakumar, Rana Sayeed, George Krasopoulos, Sander Verheule, Tudor Fulga, Ulrich Schotten, Barbara Casadei
Journal: Circulation (2014)

Background: Management of atrial fibrillation (AF) remains a challenge. AF remodels the atrial electrical properties, thereby increasing resistance to treatment. Although remodeling has long been a target for therapeutic intervention in AF, the mechanisms driving this phenomenon are incompletely understood. Methods &amp; Results: Using atrial samples from 351 patients (73 AF), and 67 goats (34 AF), we show that atrial-specific upregulation of miR31 causes dystrophin (DYS) translational repression and accelerates mRNA degradation of neuronal nitric oxide synthase (nNOS) leading to a profound reduction in NO availability. Six prediction algorithms and reporter assays established DYS and nNOS as miR-31 targets. In atrial myocytes from patients with AF (hAFm), both DYS and nNOS bind to miR-31 within the RNA induced silencing complex (RISC). In actinomycin D-treated myocytes from patients in sinus rhythm (hSRm), miR31 accelerated nNOS (but not DYS) mRNA decay. mRNA of nNOS (but not DYS) &amp; protein content of nNOS, DYS &amp; DYS associated proteins were significantly reduced in hAFm. Inhibition of miR31 in hAFm restored both DYS &amp; nNOS protein. Protection of the nNOS miR31 binding site with a target site blocker (TSB) restored nNOS mRNA and protein (but not DYS), whereas, DYS-TSB increased both DYS and nNOS protein (but not mRNA), in keeping with an effect of DYS restoration on nNOS protein stability. Indeed, K48-linked polyubiquitination of nNOS was increased in hAFm &amp; prevented by proteasome inhibition with MG132. NOS: inhibition (SMTC, 100 nmol) or transfection with a miR31 mimic was employed to evaluate the impact of these findings on atrial electrical properties. Both interventions shortened action potential duration (APD90) and abolished rate-dependency of the APD90 in hSRm but not in hAFm. By contrast, miR31 inhibition restored APD &amp; APD rate-dependency in hAFm (both reversed by SMTC) but had no effect on hSRm. In mice (n=126), nNOS gene deletion or inhibition shortened atrial APD90 &amp; lead to a 2-fold increase in AF inducibility in response to atrial burst pacing. Conclusions: These findings identify atrial-specific upregulation of miR31 in human AF as a key mechanism causing atrial loss of dystrophin and nNOS, which, in turn, lead to the electrical phenotype begetting AF.
Outcomes of dacrocystorhinostomy in patients with head and neck tumors
Authors: R. Diba, H. G. Saadati, B. Esmaeli
Journal: Journal of Clinical Oncology (2004)

5584 Background: To evaluate the outcomes of dacryocystorhinostomy (DCR) in patients with head and neck tumors. Methods: The clinical records of all 31 patients with head and neck tumors who underwent DCR for nasolacrimal duct blockage at M.D. Anderson Cancer Center between 1999 and 2003 were retrospectively reviewed for outcome and complications of DCR. Results: Nasolacrimal duct blockage was diagnosed in 35 eyes of 31 patients. The tumor diagnoses were as follows: squamous cell carcinoma (SCCA), 18 patients (16 had paranasal-sinus SCCA and 2 had skin SCCA); chondrosarcoma, 3; sinonasal carcinoma, 2; adenoid cystic carcinoma, 2; sinonasal papilloma, 2; esthesioneuroblastoma, 1; hemangiopericytoma,1; ameloblastoma,1; and ostoesarcoma,1. Twenty-one patients had a maxillectomy and 7 patients had other sinus surgeries before DCR. Six patients had had silicone intubation at the time of maxillectomy but later developed epiphora and nasolacrimal duct blockage. Ten patients had radiotherapy and 14 had chemotherapy and radiotherapy before DCR. The mean time between completion of radiotherapy and DCR was 24 months (median, 31.5 months), and the mean time between completion of chemotherapy and DCR was 21.5 months (median, 12.5 months). All 31 patients (35 eyes) experienced improvement of epiphora after DCR, but in 4 patients (4 eyes), epiphora recurred during the study period. Probing and irrigation in these 4 patients revealed recurrent nasolacrimal duct blockage. In 1 of these 4 patients, tumor recurrence in the nasal cavity was the cause; he subsequently underwent a total rhinectomy. In another patient, recurrent blockage was due to extrusion of the Pyrex glass tube, which was later replaced. The other 2 patients with recurrent blockage elected not to have additional surgery. None of the patients who had had radiotherapy developed osteoradionecrosis. Two patients had mild wound infections, which resolved after 1 week of systemic antibiotic therapy. Conclusions: DCR alleviates nasolacrimal duct blockage in the majority of patients with head and neck tumors with this side effect. No significant financial relationships to disclose.
Reply from Authors re: Tahlita C.M. Zuiverloon, Ellen C. Zwarthoff. Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We Moving Forward? Eur Urol 2016;69:201–2
Authors: Ashish M. Kamat, Diana L. Urbauer
Journal: European Urology (2015)
Laparoscopic renal cryoablation of small renal tumors: An alternative treatment option in elderly patients at high risk
Authors: J. Hwang, R. E. Weiss, R. A. Morton
Journal: Journal of Clinical Oncology (2005)

4767 Background: Minimally invasive management of small renal tumor is a reasonable alternative to open surgery in select patients. We determined the clinical utility and safety of laparoscopic renal cryoablation in elderly patients at high risk. Methods: Since December 2003, a total of 16 patients underwent laparoscopic renal cryoablation, of which 12 were considered elderly and at high risk, as defined by age 70 years or greater and American Society of Anesthesiologists (ASA) classification of 3 or greater. All patients had a solitary renal tumor measuring 2.5 to 4cm in maximal diameter (mean of 3cm). We retrospectively examined intraoperative parameters, perioperative complications and postoperative course in this cohort. Results: Median age of the 12 patients was 80 years (range 70 to 87). ASA class was 3 in all patients. Depending on the location of renal tumors, a retroperitoneal (6), transperitoneal (5) and a combined retroperitoneal/transperitoneal (1) approach was used. Laparoscopic ultrasound was utilized to guide a cryoprobe placement and to monitor ablation process in all cases. Mean operative time and intraoperative blood loss were 200 minutes (range 150 to 270) and 109 cc (range 50 to 400), respectively. The median hospital stay was 2 days (mean 2.4, range 2 to 4). Minor and major complications developed in 3 and 1 case(s), respectively. No patient died in the perioperative period and there were no re-hospitalization upon discharge. There has been no disease recurrence to date. Conclusions: Our results support the safety of laparoscopic renal cryoablation in elderly patients at high risk. Although watchful waiting is usually recommended in this population, a minimally invasive option such as cryoablation may be a reasonable and acceptable alterative in elderly patients with enlarging tumors during observation. No significant financial relationships to disclose.
Abstract #4440: BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells
Authors: Moltira Promkan, Guangming Liu, Pimpicha Patmasiriwat, Subhas Chakrabarty
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

BRCA1 is a multi-functional tumor-suppressive protein and much of its function is not fully understood. In this study we used a shRNA approach to probe the function of BRCA1. Knocking down BRCA1 expression by shRNAs in the wild type BRCA1 human breast cancer MCF-7 and MDA-MB-231 cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21/Waf1 and p27Kip1 expression. The expression of the anti-apoptotic protein survivin, on the other hand, was significantly up-regulated with a concurrent decrease in cellular sensitivity to paclitaxel. We also found that cells harboring endogenous mutant or defective BRCA1 (MDA-MB-436 and HCC1937) were highly proliferative and expressed a relatively low level of p21/Waf1 and p27Kip1 by comparison to wild type BRCA1 cells. Cells harboring mutated BRCA1 also expressed a high level of survivin and were relatively resistant to paclitaxel by comparison to wild type cells. It is concluded that the tumor-suppressive function of BRCA1 is intimately linked to the attenuation of malignant cell behavior. BRCA1 functions to promote the expression of p21/Waf1 and p27Kip1 but inhibit the expression of survivin. Loss of BRCA1 expression leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4440.
Patients with Advanced Non–Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials?
Authors: Charles Lim, Mike Sung, Frances A. Shepherd, Nazanin Nouriany, Magdalena Sawczak, Tuhina Paul, Nicole Perera-Low, Andrea Foster, Dianne Zawisza, Ronald Feld, Geoffrey Liu, Natasha B. Leighl
Journal: Journal of Thoracic Oncology (2016)
TCT-470 Manual Thrombectomy during Primary Percutaneous Coronary Intervention Can Preserve the Index of Microcirculatory Resistance in Patients with Anterior ST-Segment Elevation Myocardial Infarction
Authors: Seong Ill Woo, Ji Hoon Jang, Soo Han Kim, Dae-Hyeok Kim, Keum-Soo Park, Sang-Don Park, Sung-Hee Shin, Dong-Hyeok Yang
Journal: Journal of the American College of Cardiology (2012)
TCT-42 Long-term Safety and Efficacy of Percutaneous Coronary Intervention With Stenting and Coronary Artery Bypass Surgery for Left Main Disease: Final Five-year Follow-up of the SYNTAX Trial
Authors: Patrick Serruys, Grzegorz Religa, Witold Ruzyllo, Elisabeth Ståhle, Antonio Colombo, Michael Mack, A. Pieter Kappetein, Marie-Claude Morice, David Holmes, Ted Feldman, Keith Dawkins, Friedrich Mohr
Journal: Journal of the American College of Cardiology (2012)
PUF60: a prominent new target of the autoimmune response in dermatomyositis and Sjögren's syndrome
Authors: David F Fiorentino, Matthew Presby, Alan N Baer, Michelle Petri, Kerri E Rieger, Mark Soloski, Antony Rosen, Andrew L Mammen, Lisa Christopher-Stine, Livia Casciola-Rosen
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> Autoantibodies are used clinically to phenotype and subset patients with autoimmune rheumatic diseases. We detected a novel 60 kDa autoantibody specificity by immunoblotting using a dermatomyositis (DM) patient9s serum. Our objective was to identify the targeted autoantigen and to evaluate disease specificity and clinical significance of this new autoantibody. <h3>Methods</h3> A new 60 kDa specificity was detected by immunoblotting HeLa cell lysates. The targeted autoantigen was identified as poly(U)-binding-splicing factor 60 kDa (PUF60) using (i) a human protein array and (ii) two-dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing. Anti-PUF60 antibodies were assayed by ELISA using sera from patients with primary Sjögren9s syndrome (SS; n=84), systemic lupus erythematosus (SLE; n=71), DM (n=267), polymyositis (n=45), inclusion body myositis (n=45) and healthy controls (n=38). <h3>Results</h3> PUF60 was identified as a new autoantigen. Anti-PUF60 antibodies were present in 25/84 (30%) patients with SS, 6/71 (8.5%) patients with SLE and 2/38 (5.0%) control subjects (SS vs controls, p=0.002; SLE vs controls, p=0.711). Anti-PUF60 antibodies were present in 48/267 (18.0%) patients with DM versus 4/45 (8.9%) and 5/45 (11.1%) patients with inclusion body myositis and polymyositis, respectively. The antibody was significantly associated with anti-Ro52 antibodies, rheumatoid factor and hyperglobulinemia in the patients with primary SS. In patients with DM, the antibody was associated with anti-transcription intermediary factor 1 gamma seropositivity and Caucasian race. <h3>Conclusions</h3> PUF60 represents a novel autoantigen in patients with SS and DM. PUF60 antibodies are associated with distinct clinical features and different immune responses in different diseases.
Unusual Manifestions of B-Cell Disorders
Authors: Monika-H. Schmid-Wendtner, Christian Sander, Matthias Volkenandt, Clemens-M. Wendtner
Journal: Journal of Clinical Oncology (1999)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1999.17.3.1083a Journal of Clinical Oncology - published online before print September 21, 2016 Unusual Manifestions of B-Cell Disorders Monika-H. Schmid-WendtnerxMonika-H. Schmid-WendtnerSearch for articles by this author , Christian SanderxChristian SanderSearch for articles by this author , Matthias VolkenandtxMatthias VolkenandtSearch for articles by this author , Clemens-M. WendtnerxClemens-M. WendtnerSearch for articles by this author Show More University of Munich, LMU Munich, Germany https://doi.org/10.1200/JCO.1999.17.3.1083a First Page Full Text PDF Figures and Tables © 1999 by American Society of Clinical Oncology
Predictive significance of thymidylate synthase and dihydropyrimidine dehydrogenase levels in patients with completely resected colorectal cancer receiving adjuvant 5-fluorouracil therapy
Authors: S. A. Jensen, B. Vainer, J. B. Sorensen
Journal: Journal of Clinical Oncology (2005)

3629 Background: Cytotoxic effect of 5-FU is mediated through competitive binding to thymidylate synthetase (TS), leading to thymine depletion. 5-FU is catabolized by dihydropyrimidine dehydrogenase (DPD). It is speculated that tumorcells with high levels of TS or DPD will be less sensitive to 5-FU therapy. Aim. The primary objective was to evaluate the predictive significance of TS and DPD levels in colorectal tumors on overall survival following complete resection and adjuvant 5-FU therapy. Method: This is a retrospective study among consecutive patients completely resected for colorectal cancer stage III and treated with adjuvant 5-FU according to the Mayo-regimen. The intensity of TS and DPD were scored (0–3) using immunohistochemical staining Proportion of TS positive tumorcells were counted at the luminal surface of the tumor and at the border of tumor invasion of normal tissue, and analysed for the predictive significance to overall survival using Cox proportional hazard linear regression analysis. Results: A total of 190 patients were included. Sixty patients have deceased during 9 years of follow up. In the multivariate analysis T-stage (p=0.001), N-stage (p=0.003) and performance status (p=0.02) were significant prognostic factors, while tumor site (p=0.28), age (p=0.36), intestinal perforation (p=0.23), perineural tumorcells (p=0.26), intravascular tumorcells (p=0.50), differentiation grade (p=0.35) and histologic type (p=0.44) were non significant. The intensity of TS (p=0.18) and proportion of TS positive tumorcells (p=0.25) at the site of tumor invasion of normal tissue were better predictors for survival than the intensity of TS (p=0.64) and proportion of TS positive tumorcells (p=0.96) at the luminal surface of the tumor. The DPD intensity of tumorcells turned out not to predict overall survival (p=0.68). Conclusions: Levels of TS and DPD enzymes in colorectal tumors were not predictive factors of overall survival of adjuvant 5-FU therapy in patients at high risk of recurrence of resected colon carcinoma. No significant financial relationships to disclose.
<i>Notes from the Field</i>: Group A Streptococcal Pharyngitis Misdiagnoses at a Rural Urgent-Care Clinic — Wyoming, March 2015
Authors: Alexia Harrist, Clayton Van Houten, Stanford T. Shulman, Chris Van Beneden, Tracy Murphy
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Group A Streptococcus (GAS) is the most common bacterial cause of pharyngitis, implicated in 20%-30% of pediatric and 5%-15% of adult health care visits for sore throat (1). Along with the sudden onset of throat pain, GAS pharyngitis symptoms include fever, headache, and bilateral tender cervical lymphadenopathy (1,2). Accurate diagnosis and management of GAS pharyngitis is critical for limiting antibiotic overuse and preventing rheumatic fever (2), but distinguishing between GAS and viral pharyngitis clinically is challenging (1). Guidelines for diagnosis and management of GAS pharyngitis have been published by the Infectious Diseases Society of America (IDSA)* (1). IDSA recommends that patients with sore throat be tested for GAS to distinguish between GAS and viral pharyngitis; however, IDSA emphasizes the use of selective testing based on clinical symptoms and signs to avoid identifying GAS carriers rather than acute GAS infections (1). Therefore, testing for GAS usually is not recommended for the following: patients with sore throat and accompanying symptoms (e.g., cough, rhinorrhea) that strongly suggest a viral etiology; children aged <3 years, because acute rheumatic fever is extremely rare in this age group; and asymptomatic household contacts of patients with GAS pharyngitis (1). IDSA recommends penicillin or amoxicillin as the treatment of choice based on effectiveness and narrow spectrum of activity. To date, penicillin-resistant GAS has never been documented (1).
Abstract 13420: Concerns About Implantable Cardioverter Defibrillator Shocks Mediate the Relationship Between Shocks and Psychological Distress
Authors: Ingela Thylen, Anna Strömberg, Debra Moser, Misook Chung
Journal: Circulation (2014)

Background:  Although most implantable cardioverter defibrillator (ICD) patients cope well, fears about receiving ICD shocks have been identified as a major determinant of psychological distress. The relationships among ICD-related concerns, receipt of defibrillating shocks, and symptoms of anxiety and depression have not been investigated. Our objectives were to (1) describe ICD-related concerns, and (2) examine whether the relationships between receipt of defibrillating shocks and psychological distress were mediated by patients’ concerns related to their ICD.   Methods and Results:  All Swedish ICD-recipients were invited to this cross-sectional correlational study; 3,067 completing the survey (55% response). Their mean age was 66+11 years, and 80% were male. One third (35%) had received defibrillating shocks, and 26% had high ICD-related concerns. Regression analyses demonstrated that having received at least one shock significantly predicted symptoms of anxiety and depression (OR 1.58 and OR 3.04, respectively). The association between receipt of shocks and psychologically distress were mediated by high ICD-related concerns which explained 68% of the relationship between shocks and symptoms of anxiety, and 54% of the relationship between shocks and symptoms of depression, see Figure 1.   Conclusion:  Having high ICD-related concerns has a bigger impact on psychological distress than receipt of an actual shock. Screening for ICD-related concerns in clinical practice may identify patients at risk of psychological distress, which could provide a specific target for intervention. Interventions tailored to individual patients’ needs can - besides addressing device-related education and anxiety about shocks - also include relaxation and stress management, cognitive restructuring, social support and/or group discussions, and exercise programs.