tbuckley/cabot-search huggingface dataset:
H1N1 influenza – A second wave? The experience from a large teaching hospital in the UK
Authors: Dhruv Parekh, Judith Brebner, Chirag Dave
Journal: European Respiratory Journal (2011)

Introduction:  The new H1N1 influenza (pH1N1) virus largely ran its course by August 2010 as the WHO declared the pandemic to be over, fortunately without causing as much devastation as provisionally predicted. However the impact of the outbreak on our healthcare system was considerable. In the post -pandemic period, although the rates of pH1N1 have been reported to be lower the risk of severe illness caused by pH1N1 remains. This epidemiological study reflects our experience in a large teaching hospital of the significant morbidity and mortality associated with admission to hospital with H1N1 infection during the recent flu season.   Methods:  We retrospectively analysed the electronic records for all patients admitted with H1N1 infection between 1st November 2010 and 31st January 2011 to identify patient demographics, length of stay, co-morbidity and outcome.   Results:  280 patients were identified (mean age 39.5) with an average length of stay of 6.35 days; mortality 4%. A third had no co-morbidities. Overall 37 (13.2%) of patients required respiratory support (18 intubated, 19 NIV/CPAP). This is comparable to the pandemic of 2009 when 10–30% of laboratory confirmed hospitalised patients required critical care. 11 patients died (mean age 55; time to death 8.3 days) of those 18% had no previous medical history; the rest had co-morbidities respiratory 45%, cardiovascular 18%, haematological malignancy 9%, obesity 9% and pregnancy 9%.   Conclusions:  Although the virus seems to be taking on the behaviour of the seasonal flu our data suggests the threat of H1N1 continues and has a predilection for severe rapid disease in the young, healthy and same high risk groups as previously identified.
Improved therapeutic index of a mitomycin-C (MMC) prodrug formulated in pegylated liposomes: Studies in human xenograft tumor models of gastrointestinal (GI) origin.
Authors: A. A. Gabizon, H. Shmeeda, Y. Amitay, J. Gorin, O. Ohne
Journal: Journal of Clinical Oncology (2010)

e13628 Background: A MMC lipid-based prodrug (MLP) formulated in pegylated liposomes (PL-MLP) was previously reported to have significant antitumor activity and reduced toxicity in mouse tumor models (Clin Cancer Res 12:1913-20, 2006). MLP is activated by thiolysis releasing MMC which rapidly dissociates from liposomes. The purpose of this study was to examine the plasma stability, pharmacokinetics, in vivo toxicity, and antitumor activity of PL-MLP in human xenograft models of GI-derived tumors. Methods: MLP was incorporated with nearly 100% efficiency in pegylated liposomes with hydrogenated phosphatidylcholine as the main component with or without cholesterol (Ch). Mean vesicle size was 45-65 nm for liposome preparations downsized by homogenization, and 80-100 nm for those downsized by extrusion, the latter displaying narrower polydispersity. MLP to phospholipid molar ratio was 5% (∼20 μg MMC-equivalents/μmol). Therapeutic studies were carried out in 3 tumor models (HCT15 colon Ca, N87 gastric Ca, and Panc-1 pancreatic Ca) implanted s.c. in CD1 nude mice. Treatment was administered i.v. into mice with established tumors. Results: PL-MLP was very stable when incubated in plasma, and whole blood with a maximum of 5% of MLP undergoing activation to free MMC. In the presence of a strong reducing agent (dithiothreitol, 0.5 mM), MLP was massively activated to free MMC. Pharmacokinetic studies in mice revealed huge differences in key parameters (t, Cl, Vss) between free MMC and PL-MLP. The longest t were observed for extruded and/or Ch-containing preparations. PL-MLP was ∼3-fold less toxic than free MMC at MMC-equivalent doses. PL-MLP was significantly more effective in delaying tumor growth and resulted in more tumor regressions than irinotecan in the HCT15 and N87 models, and than gemcitabine in the Panc-1 model. Conclusions: Delivery of MLP in pegylated liposomes is more effective than conventional chemotherapy used in the treatment of GI-derived tumor models, and may represent an effective tool for treatment of these malignancies in the clinical setting with improved safety over free MMC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Teva Teva
Whole Exome Sequencing of Acute Myeloid Leukaemia Patients Identifies Somatic and Germline Mutations in Fanconi Anaemia Genes
Authors: Kyaw Zeya Maung, James X Gray, Paul J Leo, Mahmoud Bassal, Anna L Brown, Sarah C Bray, Ing Soo Tiong, Chung H Kok, Andrew Deans, Mhairi Marshall, Brooke Gardiner, Evgeny A Glazov, Paula Marlton, Devinder Gill, Luen Bik To, Ian D Lewis, Richard J D'Andrea, Thomas J Gonda
Journal: Blood (2014)
Feasibility of a urine-based DNA methylation assay for early detection of bladder cancer
Authors: Isabelle Renard, J. Kelly, Catherine Collette, C. Naômé, Hubert Nicolas, E. Zwarthoff, J. Straub, W. Van Criekinge, L. Suraparaju, Katia Bierau, David Waltregny
Journal: Clinical Cancer Research (2007)

A62  Introduction: Bladder cancer is the fourth most common cancer in men, often seen in older men with a history of smoking, and the eighth most common cancer in women. In the U.S. and EU, there are >160,000 new cases and >48,000 bladder cancer-related deaths each year. While the five-year survival rate for early-stage bladder cancer is high, there are significant challenges for early detection as well as monitoring for disease recurrence or progression, which can occur in up to 70% of cases. A DNA methylation assay with high sensitivity and specificity could help to identify those patients with bladder cancer, either initially or due to recurrence, while reducing unnecessary invasive cystoscopies.  Materials and Methods: Marker identification: Candidate genes were identified using re-expression profiles of bladder cancerous cell lines. Promoter sequences were linked with gene expression to identify valid epigenetically silenced genes. An established pharmacologic unmasking strategy (5-aza-2’-deoxycytidine (DAC) and trichostatin A (TSA)) for re-expression analysis of epigenetically targeted genes was combined with proprietary advanced bioinformatics tools to identify genes prone to promoter methylation. Marker validation: Differentially methylated genes were validated in tissue using real-time methylation specific PCR (real-time MSP). Best performing tissue markers were selected for testing DNA from urine samples. Urine sample collection, preparation and processing: Prospective randomly collected urine samples from multiple centers in Belgium, UK and The Netherlands are used in the present study. DNA is isolated using a standard DNA isolation method and standard equipment and bisulphite modified using a commercially available kit. Analyte quantitations are done using real-time MSP.  Results: The most differentially methylated genes were validated in tissue using real-time MSP. Of those, a combination of methylation markers reliably detected Bladder cancer in an independent tissue test set. A multicenter trial has been initiated in 2006. In this trial symptomatic patients, attending a urology clinic and ultimately diagnosed with bladder cancer or other non-malignant urological disorders, provided a urine sample for use in real-time MSP analysis. The trial is expected to enroll 600 individuals within 2 years. Best performing tissue markers were assessed on available urine samples from this ongoing trial. Initial data analysis confirmed that a combination of methylation markers has strong performance characteristics to correctly identify patients with bladder cancer.
Chemotherapy (CT) versus hormone therapy (HT) as neoadjuvant treatment in luminal breast cancer: A multicenter, randomized phase II study (GEICAM/2006-03).
Authors: E. Alba, L. Calvo, J. Albanell, J. De la Haba, J. Chacon, A. Arcusa Lanza, P. Sanchez Rovira, A. Plazaola, J. Lopez Garcia-Asenjo, A. Lluch
Journal: Journal of Clinical Oncology (2010)

500 Background: Luminal breast cancer is a highly endocrine responsive disease. However, the therapeutic benefit of CT in this population is not fully characterized. This study investigates the value of CT versus HT in this luminal subgroup in a neoadjuvant setting. Methods: Patients (Pt) with operable breast cancer (T2/T3) and immunophenotypically defined luminal disease (ER+/PR+/HER2-/cytokeratin 8/18+ assessed in a central laboratory) were recruited. Pts were randomized to CT (epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles [cy] followed by docetaxel 100 mg/m2 × 4 cy [EC-T]) or HT (exemestane 25 mg daily × 24 weeks [combined with goserelin in premenopausal pts]). The primary end point was clinical response measured by magnetic resonance image. Secondary end points were pathological complete response (pCR), toxicity, type of surgery, and axillary status at surgery. Adjuvant treatment was provided in an individualized manner. Results: 95 pts were randomized (47 CT, 48 HT) from March 07 to December 08. Pts characteristics were well balanced between arms. Median age was 51 years (32-74), 54% of pts were premenopausal, 23% grade I, 17% grade III, 76% T2 and 55% N0. Clinical response rate was 66% for CT (13% complete response [CR] and 53% partial response [PR]) and 48% for HT (6% CR and 42% PR) (p = 0.07). 3 pts with CT and 0 with HT achieved a pCR (p = NS). pN0 rate was similar between arms (CT: 36%, HT: 29%; p = 0.47). Mastectomy rate was similar in both arms (CT: 49%, HT: 35%; p = 0.18). We performed an unplanned analysis based on Ki67 levels (cut off of 10%). Similar clinical response was seen between arms in pts with low Ki67 (CT: 63%, HT: 58%; p = 0.7); pts with high Ki67 had a better response with CT (67% vs. 42%; p = 0.07). Grade III-IV toxicity (excluding amenorrhea) was more frequent with CT (47% CT vs. 9% HT; p = 0.0001). Conclusions: Luminal immunophenotype is not sufficient to identify patients that do not benefit from neoadjuvant chemotherapy. Our trial shows a trend to induce more clinical responses with CT. This trend is bigger in pts with high Ki67 levels. However responses seem to be similar in pts with low Ki67; further studies are warranted to confirm this finding. No significant financial relationships to disclose.
Bromocriptine in Parkinson disease.
Authors: A N Lieberman, M Goldstein
Journal: Pharmacological Reviews (1985)

Bromocriptine is an ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors. Bromocriptine, unlike other dopamine agonists, has mixed "agonist-antagonist" properties at these receptors. The striatal dopamine receptors exist in two different affinity states: a low and a high affinity state. Bromocriptine, unlike other dopamine agonists, does not differentiate between the low and the high affinity state of the D2 receptors, and bromocriptine does not induce a conformational change in these receptors. Bromocriptine, in low doses, is effective in patients with mild to moderate Parkinson's disease, while bromocriptine in higher doses is needed in patients with advanced disease. Both in low doses and in high doses, bromocriptine combined with levodopa is usually more effective than bromocriptine alone. The efficacy of low dose (5-30 mg/day) and high dose (31-100 mg/day) bromocriptine alone and with levodopa was examined in 27 studies encompassing 790 patients. Forty-six % of the studies were done in a double blind manner. In four studies of 79 patients, low dose bromocriptine (16 mg/day) without levodopa resulted in improvement in 58% of the patients. Only 9% of the patients experienced adverse effects. Most of the patients (63%) and mild or moderate Parkinson disease. In seven studies of 143 patients, high dose bromocriptine (56 mg/day) without levodopa resulted in improvement in 62% of patients, but with 27% having adverse effects. Most of these patients (77%) had mild or moderate disease. Diurnal oscillations in performance, the "wearing off" or "on-off" effect, were not seen during treatment with bromocriptine alone. In nine studies of 201 patients, low dose bromocriptine (23 mg/day) and levodopa resulted in improvement in 71% of patients with 26% having adverse effects. Most of these patients (66%) had advanced disease, and many had diurnal oscillations in performance. In seven studies of 367 patients, high dose bromocriptine (48 mg/day) and levodopa resulted in improvement in 58% with 37% having adverse effects. Most of these patients (85%) had advanced disease. The increased effectiveness of bromocriptine in combination with levodopa may be explained as follows. Bromocriptine by itself does not discriminate between the low and the high affinity states of the dopamine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Patient attitudes regarding payment for participation in a phase I cancer clinical trial
Authors: A. Gibbs, J. F. Merz, L. Gore, C. L. O'Bryant
Journal: Journal of Clinical Oncology (2007)

6573 Background: Research industry practice reimburses healthy phase 1 study subjects and yet cancer patients who participate in a phase 1 study are rarely reimbursed. The ethical problems of disproportionate risk/benefit ratio and coercive informed consent are cited as reasons for not paying cancer study subjects. The purpose of this study is to determine if payment to participate in a phase 1 clinical trial affects a cancer subject's willingness to participate (WTP) in a clinical trial and to determine if any payment would reduce the therapeutic misconception. Methods: Eligible adults had consented to participate in a phase 1 clinical trial of an investigational drug at UCCC but had not yet initiated treatment. Subjects were identified by UCCC staff, consented to participate in this study, and then administered a questionnaire by phone. Primary analyses were descriptive in nature. Results: Thirty subjects were enrolled. The median age was 57 years (range 30–76); 53% were female; 97% were Caucasian; 77% had at least some college education; 47% had an annual household income of &lt; $50,000. When asked an open-ended question, 53% of subjects stated that the main purpose of the phase 1 trial in which they consented to participate was efficacy. The majority of subjects (80%) did not think they should be paid to participate in a phase 1 cancer trial. Most subjects (73%) expected to benefit from phase I study participation and greater than 80% of subjects stated that payment would not change their perception or hope of benefit. There was a minor trend towards increased WTP with increased reimbursement or payment. Thirty-seven percent of subjects acknowledged that payment might affect what side effects they report. Conclusions: While payment appeared to have little or no affect on a cancer subject's expectation of benefit from a phase 1 trial, WTP increased slightly with increasing payment. Given these results, it seems that payment would not reduce the therapeutic misconception related to participation in phase 1 cancer trials. This study should be expanded to confirm these findings. No significant financial relationships to disclose.
LPL Is the Strongest Prognostic Factor in a Comparative Study of RNA-Based Markers in Chronic Lymphocytic Leukemia.
Authors: Mohd Arifin Kaderi, Meena Kanduri, Mahmoud Mansouri, Anne Mette Buhl, Marie Sevov, Nicola Cahill, Rebeqa Gunnarsson, Mattias Jansson, Karin Ekström Smedby, Henrik Hjalgrim, Gunnar Juliusson, Jesper Jurlander, Richard Rosenquist
Journal: Blood (2009)
Clinically robust methods for acquiring and analyzing DCE-MRI (Dynamic Contrast Enhanced Magnetic Resonance Imaging) data using noninvasive approaches to the measurement of pharmacodynamic effects (PDE) of antiangiogenic agents (AA)
Authors: C. A. Presant, W. Wolf, V. Waluch, P. M. Colletti, A. Barlev, A. J. Parker, C. L. Wiseman, P. S. Kennedy, B. Leberthon, V. P. Israel
Journal: Journal of Clinical Oncology (2004)

3152 Background: Robust methods are needed that can monitor patients (pts) being treated with AA in a clinical environment. While DCE-MRI is an effective method for monitoring the PDE of AA (ASCO 22, 824, 2003), different methods are used to acquire and then analyze the data obtained. Administration of an MRI contrast agent (COA) allows the visualization of the vasculature into which that solute distributes, and using a fast acquisition method, one monitors the rate of influx of blood into tumor and other organs, as well as the retention and the rate of efflux. We believe that high temporal resolution (e.g. 1 second) is critical to capture the early influx phase, which appears to be most critically associated with pt response. Methods: Upon COA administration as a bolus (1 ml Gd-DTPA/10 lbs of pt-weight, at 2 ml/sec), MR images are acquired using a volume sequence with a temporal resolution of 1 sec for the first 2 min, followed by data acquisition every 15–30 sec for another 20 min. Data analysis is performed by a direct measurement of the time course of proton enhancement using ImageJ, an image analysis software developed at the NIH (http://rsb.info.nih.gov/ij) and estimating the changes in the rates of the influx (ICAR, Initial Contrast Accumulation Rate) and of the efflux (DCAR, Delayed Contrast Accumulation Rate) in any desired Region-of-Interest. Prior alternative methods relied on the AUC and compartmental analyses (COMP) approaches. Results: The association between the change in the ICAR in pts treated with Taxotere and response, time-to-progression and survival was p=0.006, 0.006 and 0.02, respectively. In a representative patient the ICAR values of 6 slices were 9.8±1.75 and the ratio of k12/k21 were 9.5±0.63. Detailed comparisons of analyses between the ICAR and COMP will be presented. Conclusions: While both ICAR and COMP provide statistically valid data, the ICAR slope change provides an effective, robust and reliable method that should be used in monitoring pts for PDE of AA. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; Aventis
Systemic telomerase gene therapy delivered via targeted lipidic nanoparticles
Authors: A. Goldkorn, B. Hann, M. Hayes, D. C. Drummond, D. B. Kirpotin, K. Peth, J. D. Marks, E. H. Blackburn, J. W. Park
Journal: Journal of Clinical Oncology (2006)

13025 Background: Most human cancers possess elevated telomerase activity that promotes proliferation. We developed 2 telomerase-targeting gene constructs: telomerase RNA containing a mutated template sequence (MT-hTer), and short interfering RNA (siRNA) targeting endogenous wild type telomerase RNA. When co-expressed in cancer cell lines and xenografts, MT-hTer/siRNA synergizes to cause rapid cell death (Li, S et al. Cancer Research 2004). Here, we tested the in vivo efficacy of MT-hTer/siRNA delivered systemically via antibody-targeted lipidic nanoparticles in a breast cancer metastasis model. Methods: Nude mice received intracardiac injection of luc+MCF7-C18 breast carcinoma cells ectopically overexpressing HER2 and luciferase. After 3 days, the mice were treated with a single 100 μg i.v. injection of either MT-hTer/siRNA-GFP or control (GFP-only) plasmid formulated into lipid-DNA nanoparticles conjugated to an internalizing anti-HER2 single chain antibody (Genosphere, TM) (Hayes, M et al. Gene Therapy 2005). A third group received saline (PBS) as a vehicle control. Cancer progression was monitored non-invasively via biophotonic imaging (Xenogen) of tumor luciferase signal. Results: By week 2 the PBS control group showed luciferase signal elevation that increased exponentially during the study. Similarly, the GFP-only control group developed significant luciferase signal elevation by week 3, with continued rise at all subsequent time points. In contrast, the MT-hTer/siRNA-GFP group experienced a decreased luciferase signal by week 2, which remained consistently low throughout the experimental time course. There were no observed treatment-related toxicities. Conclusions: In pilot in vivo studies, telomerase therapy dramatically inhibited tumor formation in mice after systemic delivery with cancer-targeting lipid-DNA nanoparticles. Expanded preclinical studies are underway. [Table: see text]
The single nucleotide polymorphism MDM2-SNP309 influences sensitivity of B-CLL cells to the non-genotoxic activator of the p53 pathway Nutlin-3a
Authors: I. Tinhofer, I. Seyfried, M. Stoecher, S. Hofbauer, P. T. Daniel, R. Greil
Journal: Journal of Clinical Oncology (2008)

14552 Background: The single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2, a negative regulator of p53, has been linked to increased cancer risk in various solid tumor models. We have recently identified the SNP309 genotype as independent prognostic factor for overall survival in B-CLL (Gryshchenko et al, JCO, accepted for publication). Nutlin-3a, a small molecule inhibitor of the p53-MDM2 interaction reactivates p53 and induces p53-dependent apoptosis. We hypothesized that sensitivity of B-CLL cells to nutlin-3a-induced apoptosis might differ between cells from SNP309 T/T, T/G or G/G carriers. Methods: The SNP309 genotype of B-CLL cells was assessed by RT-PCR. In addition, the p53 status was assessed by single-stranded conformation polymorphism (SSCP) and fluorescence-in-situ-hybridization (FISH) analysis, respectively. Sensitivity of B-CLL cells to apoptosis induced by nutlin-3a was determined by flow cytometry using annexin V-FITC/7-AAD staining. Extent and kinetics of p53 stabilization following nutlin-3a treatment was determined by Western blot analysis. Results: We observed significant induction of apoptosis in B-CLL cells treated with nutlin-3a in a dose- and time-dependent manner. The percentages of apoptotic B-CLL cells were significantly higher in B-CLL samples from SNP309 T/G or G/G as compared to T/T carriers. In addition, higher sensitivity of SNP309 T/G or G/G variants to nutlin-3a treatment was not specific for B-CLL cells, but also observed in CD19+ B-cells from healthy controls. Addition of nutlin-3a significantly increased p53 expression levels in a time-dependent manner. However, the nutlin-induced increase in p53 did not significantly differ between B-CLL cells from SNP309 T/T when compared to T/G or G/G carriers. Conclusions: Our analysis identified a cohort of patients which might particularly profit from therapeutic targeting of p53/MDM2 interactions in B-CLL. The exact molecular mechanism for the higher sensitivity of B-CLL cells from SNP309 T/G or G/G carriers to nutlin treatment has to be clarified in future studies. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche