tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) of E7389, a Halichondrin B analog with novel anti-tubulin activity: Results of two phase I studies with different schedules of administration
Authors: N. Wong, C. Desjardins, S. Silberman, M. Lewis
Journal: Journal of Clinical Oncology (2005)

2013 Background: E7389 is a synthetic analog of halichondrin B with a unique mechanism of action based on aggregation of microtubule subunits. Two Phase I studies are currently being conducted to determine the MTD, safety, and PK of a 1-hour IV infusion on Days1, 8 and 15 of a 28-day cycle (Study 101), or on Day 1 of a 21-day cycle (Study 102). The PK measurements from these studies are described. Methods: Twenty-six (101) and 18 patients (102) with advanced solid tumors were enrolled at two centers thus far. Doses ranged from 0.5 to 2.8 mg/m2 for the 101 study, and 0.25 to 4 mg/m2 for the 102 study. Blood samples were collected from Days 1 and 15 (101 only) at predetermined time points, and analyzed by LC/MS/MS. The PK parameters were estimated by non-compartmental and two-compartmental analyses. Results: 101: E7389 exhibited a bi-exponential disposition following IV administration. In summary, following intravenous administration, E7389 exhibited a rapid distribution phase with a mean ± SD t1/2 of 0.45 ± 0.20 (median: 0.39) hour, followed by a slow elimination phase with a mean ± SD t1/2 of 36 ± 12 (median: 33) hours. The mean ± SD systemic clearance (CL) and volume of distribution at steady state (Vss) were 1.7 ± 0.9 (median:1.5) L/hr/m2 and 55 ± 25 (median: 46) L/m2, respectively. Only approximately 6–7% of unchanged E7389 was excreted (0–72 hr) into the urine. 102: The disposition of E7389 follows linear kinetics over the dose range studied (0.25 to 4.0 mg/m2). Overall, following intravenous administration, E7389 plasma concentration-time profile exhibited a rapid distribution phase with a mean ± SD t1/2 of 0.40 ± 0.15 (median: 0.37) hour, followed by a slow elimination phase with a mean ± SD t1/2 of 41 ± 13 (median: 37) hours. The mean ± SD CL and Vss of E7389 were 2.0 ± 1.0 (median: 1.6) L/hr/m2 and 72 ± 27 (median: 75) L/m2, respectively. A small fraction (approximately 7%) of E7389 was excreted unchanged into the urine. Conclusions: The disposition of E7389 follows linear kinetics over the dose range studied, and the PK in patients can be characterized by an extensive volume of distribution, a slow to moderate clearance, and a slow elimination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Medical Research Institute
Prevention of chemo-induced cardiotoxicity by dexrazoxane (D)
Authors: M. Tomirotti, K. Borgonovo, R. Ratti, G. Farina, A. Scanni
Journal: Journal of Clinical Oncology (2005)

8281 Background: Anthracyclines (A) produce oxidative distress and cardiac heart failure (CHF) dose-related; D can reduce cardiotoxicity inhibiting onset of stable complex with Fe3+; we can limit the cumulative dose of doxorubicin, use analogous or liposomial anthracycline and associate D to chemotherapy (CT). Methods: From 1/2000 up today according to ’99 ASCO guidelines we treated with D 500 mg, 87 oncologic patients (pts) 72 females, median age 59,1 years (range 33–80), breast 59, NHL 21, sarcomas 3, bladder 2, tymoma 1, schwannoma 1, before various A-based CT treatments. Basal echocardiography and left ventricular ejection fraction measurement (LVEF) was performed in anamnestic cardiac disease, reaching the A-target dose, on clinical demand and at the end of treatment. 17/87 pts had previous cardiac disease: 6 infartual, 3 ischemic, 8 arytmic. Results: Before chemioprevention the median delivered doxorubicin dose was 251 mg/mq, epirubicin 379 and mitoxantrone 48; supporting with D we delivered again respectively 256 mg/mq, 262,and 34. Metastatic breast cancer is highly chemosensitive; so we treated with cardiotoxicity drugs in 1st line 17 pts, 19 in 2nd, 12 in 3rd, 5 in 4th, 5 in 5th and 3 in 6th; in 25 pts we delivered 1st line CT with A, 2nd line in 31 and 3rd in 5. LVEF was < 50% asymptomatic in 6 pts. Conclusions: We hadn’t major cardiac events in pts largely treated with A-based CT, no CHF, 6 LVEF < 50%. Actually we treated by sequential cardiotoxic CT, chemosensitive tumors obtaining prolonged survival; cardio-prevention is pivotal to maintain adequate quality of life. No significant financial relationships to disclose.
Abstract 16606: Myocardial Reloading after Extracorporeal Membrane Oxygenation Promotes Protein Synthesis and Alters Flux Through the Citric Acid Cycle
Authors: Masaki Kajimoto, Colleen M O'Kelly Priddy, Dolena R Ledee, Nancy Isern, Chun Xu, Aaron K Olson, Christine Des Rosiers, Michael A Portman
Journal: Circulation (2012)

Background: Extracorporeal membrane oxygenation (ECMO) unloads the heart providing a bridge to recovery in children after myocardial stunning. Mortality after ECMO remains high. Cardiac substrate a...
Quality of Life and Bowel Function in Locally Advanced Rectal Cancer Patients Treated with an Intensified Neoadjuvant Regimen in the Expert-C Trial
Authors: F. Sclafani, C. Peckitt, D. Cunningham, J. Capdevila, B. Glimelius, A. Cervantes Ruiperez, J. Thomas, D. Tait, G. Brown, J. Oates, I. Chau
Journal: Annals of Oncology (2014)
Videotape recording of inpatient assaults: a pilot study
Authors: D A Brizer, M L Crowner, A Convit, J Volavka
Journal: American Journal of Psychiatry (1988)

Inpatient assaults were videotaped and then characterized by tape reviewers as showing high or low hostility. Over a 2-month period, the videotape reviewers documented more than twice as many high-hostility assaults as were documented by other methods of reporting.
Abstract 18701: Sildenafil Attenuates Ethanol-Induced Myocardial Dysfunction and Cytotoxicity
Authors: Gregory R Sturz, Anindita Das, Nicholas N Hoke, Fadi N Salloum, Rakesh C Kukreja
Journal: Circulation (2013)

Background: Ethanol (EtOH) induces cardiotoxicity by increasing apoptosis, free radical formation and lipid peroxidation. Since sildenafil has potent cardioprotective effects through activation of protein kinase G, we hypothesized that treatment with sildenafil would attenuate cardiotoxicity associated with acute EtOH exposure by reducing apoptosis and preserving function. Methods and Results: Mice were treated with EtOH (3 g/kg/day, ip) ± sildenafil (0.7 mg/kg, ip) for 3 days. Cardiac function was measured in Langendorff mode. EtOH treatment decreased rate-force product (g·bpm) (270 ± 26, P &lt; 0.01) as compared to control (433 ± 23), which was preserved with sildenafil co-treatment (392 ± 38). EtOH increased myocardial apoptosis (1.42 ± 0.16%; P &lt; 0.001 vs. control 0.05 ± 0.03%), which was attenuated with sildenafil (0.05± 0.05%). Sildenafil increased myocardial PKG activity with (2.6 fold) or without EtOH (4.6 fold). To further understand the mechanism of protection of sildenafil against EtOH cardiotoxicity, primary rat cardiomyocytes were treated with 100 mM EtOH ± 10 μM sildenafil. At 18 h, necrosis (trypan blue staining); mitochondrial membrane potential (mΔΨ, JC-1; aggregates/monomer); and ROS (DCF; F488 AU) were measured. At 48 h, apoptosis was assessed by TUNEL. EtOH increased necrosis and apoptosis, which were attenuated with sildenafil (Fig 1). EtOH disrupted mΔΨ (EtOH 1.24 ± 0.17, P &lt; 0.001) and increased ROS production (EtOH 156.73 ± 36.91, P &lt; 0.01) compared to control (13.08 ± 1.78 and 28.09 ± 5.75, respectively). Sildenafil preserved mΔΨ (19.29 ± 3.01) and attenuated ROS production (12.38 ± 5.70). Knockdown of PKG with adenoviral shRNA blocked the protective effect of sildenafil whereas overexpression of PKG1α conferred similar protection against EtOH cytotoxicity (Fig 1). Conclusion: Sildenafil attenuates the EtOH cardiotoxicity through PKG-dependent maintenance of mitochondrial integrity while preserving cardiac function.
Progression-free survival in ovarian cancer patients in second remission with mucin-1 autologous dendritic cell therapy.
Authors: Heidi J. Gray, Sharron Erna Gargosky
Journal: Journal of Clinical Oncology (2014)

5504 Background: CVac is an autologous cellular therapy made by culturing autologous dendritic cells with a mucin 1 fusion protein and is intended to elicit a killer T cell response that is specific to mucin 1 over-expressing ovarian cancer cells. CAN-003 is an open label phase 2 study evaluating Cvac as compared to standard of care (SOC) with the efficacy endpoints of progression free (PFS) and overall survival (OS), as well as safety and immune monitoring. Methods: Eligible patients were stage III or IV epithelial ovarian cancer (EOC) who obtained a complete response to standard first (CR1) or second line chemotherapy (CR2).The first 7 patients were non-randomized and received Cvac (NR Cvac) for manufacturing comparison. Thereafter patients were randomized to either Cvac (10 doses over 52 weeks) or to SOC. Results: 63 patients were enrolled into the trial; 7 NR Cvac, and 29 Cvac and 27 SOC randomized. 42 patients were CR1 and 21 CR2. Overall CR1 and CR2 demographics were similar regarding tissue histology, optimal debulking and staging. 9 SAEs were reported in total. None were unexpected and only one (small bowel obstruction) was classified as unlikely-related to Cvac. PFS was not improved in CR1 with Cvac over SOC (HR=1.18, p=0.69) where as in CR2, CVac demonstrated a significant improvement in PFS; median PFS for SOC was 4.94 months; the median PFS for Cvac was not reached but is greater than 12.91 months (p=0.04). Patient blood was assessed for antibodies to mucin 1; as anticipated, none were detected. Peripheral PBMC were assessed for T cell responses to mucin 1. Mucin 1 specific CD4 and CD8 T cell responses were observed, though without a significant correlation with PFS. Conclusions: Cvac treatment was safe and showed a significant improvement in PFS in 20 EOC patients in CR2. This strong efficacy signal in the CR2 population warrants further investigation in a larger trial. Clinical trial information: NCT01068509.
Alternating cycles of etoposide plus cisplatin and VAB-6 in the treatment of poor-risk patients with germ cell tumors.
Authors: G J Bosl, N L Geller, N J Vogelzang, R Carey, J Auman, W F Whitmore, H Herr, M Morse, P Sogani, E Chan
Journal: Journal of Clinical Oncology (1987)

A phase II trial of 6 months of alternating etoposide plus cisplatin (EP) and cyclophosphamide, vinblastine, actinomycin D, bleomycin, cisplatin (VAB-6) was conducted in 41 evaluable patients in an attempt to improve the treatment results in those patients considered to have "poor-risk" germ cell tumors (GCT). Eight of 14 (57%) patients with mediastinal and retroperitoneal GCTs achieved complete remission (CR), and five (36%) remain alive and free of disease. Fourteen of 27 patients (52%) with poor-risk testicular cancer achieved CR, and ten (37%) remain alive and free of disease. Two patients with seminoma, one each with a testicular and extragonadal primary tumor, achieved durable CRs. Toxicity was tolerable, but greater than that of VAB-6 alone. The response and survival of the 39 patients with nonseminomatous tumors were found to be identical to the results of 29 patients with nonseminomatous GCTs and poor-risk characteristics who were treated with VAB-6 alone. Thus, this 6-month schedule of alternating months of chemotherapy is not recommended for patients with poor-risk GCTs. Patients with such tumors should be referred to centers conducting prospective trials, so that research seeking better therapy may continue.
Utility of Positron Emission Tomography for the Staging of Patients With Potentially Operable Esophageal Carcinoma
Authors: P. Flamen, A. Lerut, E. Van Cutsem, W. De Wever, M. Peeters, S. Stroobants, P. Dupont, G. Bormans, M. Hiele, P. De Leyn, D. Van Raemdonck, W. Coosemans, N. Ectors, K. Haustermans, L. Mortelmans
Journal: Journal of Clinical Oncology (2000)

PURPOSE: A prospective study of preoperative tumor-node-metastasis staging of patients with esophageal cancer (EC) was designed to compare the accuracy of 18-F-fluoro-deoxy-d-glucose (FDG) positron emission tomography (PET) with conventional noninvasive modalities. PATIENTS AND METHODS: Seventy-four patients with carcinomas of the esophagus (n = 43) or gastroesophageal junction (n = 31) were studied. All patients underwent attenuation-corrected FDG-PET imaging, a spiral computed tomography (CT) scan, and an endoscopic ultrasound (EUS). RESULTS: FDG-PET demonstrated increased activity in the primary tumor in 70 of 74 patients (sensitivity: 95%). False-negative PET images were found in four patients with T1 lesions. Thirty-four patients (46%) had stage IV disease. FDG-PET had a higher accuracy for diagnosing stage IV disease compared with the combination of CT and EUS (82% v 64%, respectively; P = .004). FDG-PET had additional diagnostic value in 16 (22%) of 74 patients by upstaging 11 (15%) and downstaging five (7%) patients. Thirty-nine (53%) of the 74 patients underwent a 2- or 3-field lymphadenectomy in conjunction with primary curative esophagectomy. In these patients, tumoral involvement was found in 21 local and 35 regional or distant lymph nodes (LN). For local LN, the sensitivity of FDG-PET was lower than EUS (33% v 81%, respectively; P = .027), but the specificity may have been higher (89% v 67%, respectively; P = not significant [NS]). For the assessment of regional and distant LN involvement, compared with the combined use of CT and EUS, FDG-PET had a higher specificity (90% v 98%, respectively; P = .025) and a similar sensitivity (46% v 43%, respectively; P = NS). CONCLUSION: PET significantly improves the detection of stage IV disease in EC compared with the conventional staging modalities. PET improves diagnostic specificity for LN staging.
Abstract 19016: ALK2 and ALK3 BMP Type I Receptors Are Required for the Development of Cardiac Hypertrophy
Authors: Mohd Shahid, Ester Spagnolli, Laura Ernande, Starsha Kolodziej, Claire Mayeur, Patricio Leyton, Marielle Scherrer-Crosbie, Kenneth D Bloch
Journal: Circulation (2013)

Bone Morphogenetic Proteins (BMP) signaling is required for the development of cardiac hypertrophy. BMP signaling mediates its action via BMP type I and type II receptors. We sought to determine which type I receptors are required for cardiac hypertrophy. We studied BMP signaling in neonatal rat cardiomyocytes (NRCs) stimulated with phenylephrine (PE) or isoproterenol (ISO). In comparison with untreated NRCs, PE (10 μM) and ISO (10 μM) induced hypertrophy, as reflected by increases in cell size (457±50 and 401±35 vs 254±23 μm2, p&lt;0.01) and expression of the gene encoding B-type natriuretic peptide (NPPB; 4.0±1.0 and 3.2±0.8-fold, p&lt;0.01). PE and ISO induced expression of genes specifying BMP2 (6.7±0.5 and 5.6±0.6-fold), BMP7 (4.1±0.4 and 3.6±0.9-fold), and the BMP target gene, Id-1, (3.7±0.1 and 4.2±1.0-fold, p&lt;0.001). PE and ISO also induced phosphorylation of BMP-responsive Smads 1 and 5 and increased activity of a BMP response element-luciferase reporter (14.5±0.8 and 11.9±1.1 vs 5.4±0.4, p&lt;0.01). Incubation of NRCs with the BMP inhibitors, LDN193189 (100 nM) or noggin (100 ng/ml), markedly suppressed the ability of PE and ISO to increase cell size, NPPB gene expression, and Smad1/5 phosphorylation. qRT-PCR analysis revealed that ALK2 and ALK3 were highly expressed in NRC, whereas ALK1 and ALK6 were expressed at very low levels. siRNA-mediated silencing of ALK2 or ALK3, but not ALK1 or ALK6, blocked PE-induced hypertrophy in NRCs. Using cardiomyocytes from ALK1flox/flox and ALK2flox/flox neonatal mice infected with Ad-Cre (to delete the floxed allele) or Ad-RFP (as a control) revealed that PE-induced hypertrophy requires Alk2 but not Alk1. Based on these observations, we conclude that BMP signaling is upregulated in NRCs in response to hypertrophic stimuli. ALK2 and ALK3 appear to be the BMP type I receptors which are required for the development of hypertrophy in neonatal cardiac myocytes.
Curating the Way to Better Determinants of Genetic Risk
Authors: Elizabeth G. Phimister
Journal: New England Journal of Medicine (2015)

A diagnosis of unilateral ductal carcinoma in situ and a family history of breast cancer motivated me to request genetic testing. I was primarily interested in my BRCA1 and BRCA2 sequences because certain variants in these genes confer a high risk of breast cancer. BRCA variants of unknown significance and pathogenic BRCA variants were not detected. A variant of unknown significance in a gene called MRE11A was determined to be present, but there is limited evidence that variants in MRE11A influence susceptibility to breast cancer, which raises the question of why MRE11A was included in the analysis.Three tasks must . . .
PTH-346 Permanent stoma rates as a marker of quality indicators for rectal cancer management
Authors: S Yoganathan, K Goonetilleke, S Bassiony, P Waterland, S Pandey
Journal: Gut (2015)

<h3>Introduction</h3> Permanent stoma rate continues to be one of the quality indicators for rectal cancer management. National Bowel Cancer Audit 2013 annual report quotes a non-closure rate 30% or more of “temporary” stomas in rectal cancer surgery. This is considered to be reflective of poor quality of rectal cancer care. <h3>Method</h3> A prospectively maintained data base of patients undergoing colorectal cancer resections in one of the large volume hospital trusts in the UK was analysed from 2011 to 2014 to assess the stoma rates, recanalisation and timings to reversal. The data base was verified against electronic records of radiology, endoscopy and clinic letters to ensure accuracy. <h3>Results</h3> A total of 278 patients underwent curative surgery for rectal cancer. 207 had anterior resections (74.5%), 30 Hartmanns (10.7%) and 41 (14.8%) abdomino perineal resections. Overall 53.6 per cent of rectal cancer patients had a stoma at the time of a surgical resection. This included all cases of APER and Hartman’s but in addition 28.5 per cent of all anterior resections were covered by an ileostomy. Out of the ileostomies 52.5% were reversed. The mean time to reversal was 6 months (2–14 month). The mean time delay from clinic decision to contrast enema/endocopy and actual reversal were 34.5 days and 5 months respectively. The main reasons for delayed reversal were adjuvant chemotherapy and for non reversal was that patients were still awaiting reversal although they had been seen in clinic. <h3>Conclusion</h3> Restorative resection rate <i>per se</i>(low permanent stoma rate) for low rectal cancers continues to be regarded as a national surrogate marker of surgical quality. An outcome audit is the best performance indicator for a colorectal unit. However, due consideration should be given to prevalence of ultra low rectal cancers, site of the tumour, preoperative poor sphincter function and patient fitness. Permanent stoma may not necessarily be a true depiction of quality of surgical care especially in the presence of MDT decisions where management plans are made preoperatively. <h3>Disclosure of interest</h3> None Declared.
A computer program designed to assist in NSCLC adjuvant therapy decision making
Authors: P. M. Ravdin, G. J. Davis
Journal: Journal of Clinical Oncology (2006)

7230 Background: The goal the computer program, Adjuvant! for NSCLC, is provide the health professional, and the NSCLC patient with information that might be helpful when deciding about adjuvant chemotherapy for completely resected Stage 1 to Stage 3A disease. The 4 elements of this decision are: estimates of prognosis, estimates of the efficacy of adjuvant chemotherapy, estimates of completing mortality, and estimates of toxicity. Methods: Estimates of prognosis are based on an analysis of 17, 130 patients in the SEER registry. Estimates for 5 year disease specific mortality for Stage 1A, 1B, 2A, 2B, and 3A disease are 22%, 37%, 51%, 63%, and 70%. Multivariate analysis justifies using tumor size, histologic grade, and BAC histology for refinement of prognostic estimates for Stage 1 patients. A small subgroup of Stage 1 patients (with tumors &lt; 10mm, low grade, BAC histology) could be identified with a 5 year disease specific mortality risk of &lt;10%. Estimates of the efficacy of chemotherapy were derived from meta-analyses. A proportional risk reduction of 20% is used by the program as the default efficacy estimate for platinum-based therapy. Pop-ups and help files discuss areas of uncertainty and controversy. The user has the option to adjust the default efficacy estimate to the more optimistic efficacy estimates of some of the recent trials, or to take into account some of the uncertainty as to whether adjuvant chemotherapy works as well in Stage 1 disease. SEER data shows the average NSCLC patient has competing mortality rates higher than would be suggested by chronologic age. Regimen specific risks of treatment related toxicity is given by the program. In the over 100 pages of help files there is a detailed discussion of the clinical evidence, adjuvant therapy guidelines, ongoing clinical trials, and corollary areas (radiotherapy, neoadjuvant therapy, biomarkers, etc.) Results: The program projects that for patients with favorable Stage 1 tumors the absolute OS benefit of therapy may be as low as 1% (of the same size as the risk of treatment related mortality), but for patients with Stage 2 and 3A disease the 5 yr OS benefit may be ∼10%. Conclusions: The impact of this tool on physician and patient knowledge about the adjuvant therapy of NSCLC will be presented. [Table: see text]
Abstract 165: Palmitate Induces Dose-Dependent Apoptosis in Chick Embryo Cardiomyocytes
Authors: Charles C Oh, Jennifer Levy, Wuqiong Ma, Peter Reaven, Raymond Migrino, Daniel Franco, Kent Thornburg
Journal: Circulation Research (2012)

BACKGROUND: In morbid obesity and type 2 diabetes saturated fatty acid (SFA) levels are markedly increased. Palmitate, a SFA, crosses the placenta easily and may affect embryos of diabetic mothers. Palmitate induces inflammation and apoptosis in many cell types including cardiomyocytes. Transient cardiomyopathy can develop in offspring of diabetic mothers. We are testing the hypothesis that palmitate will increase apoptosis in chick embryo cardiomyocytes, making it vulnerable for later disease. METHODS: Hearts from chick embryos at Hamburger Hamilton stage 31 were harvested and digested into single cells using trypsin then plated. After 48 h of growth, cells were exposed to free palmitate (at ∼2.3:1, FFA:albumin ratio) at high physiological concentrations for 24 h. Apoptosis was measured with Annexin V and cell necrosis with propodium iodide using flow cytometry. RESULTS: Apoptosis was markedly elevated in chick embryo cardiomyocytes exposed to palmitate in a dose dependent manner (see Figure). Percentage of apoptotic cells increased from 11.9% in 0 μM palmitate to 32.0% and 44.1% in 150 μM and 300 μM respectively. The percentage of cells demonstrating non-apoptotic necrosis was low and did not change with increasing palmitate concentration. CONCLUSIONS: In chick embryo cardiomyocytes apoptosis is increased in a dose-dependent manner by brief exposure to palmitate. This may have important implications for intrauterine cardiac development in pregnant diabetic mothers and needs to be further explored.