3,010 research outputs found
ROMANA 3: A phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Background: Cancer anorexia-cachexia is a debilitating condition frequently observed in NSCLC patients, characterized by decreased body weight, reduced food intake, and impaired quality of life. Anamorelin, a novel selective ghrelin receptor agonist, has anabolic and appetite-enhancing activities. Patients and methods: ROMANA 3 was a safety extension study of two phase 3, double-blind studies that assessed safety and efficacy of anamorelin in advanced NSCLC patients with cachexia. Patients with preserved Eastern Cooperative Oncology Group ≤ 2 after completing 12 weeks (w) on the ROMANA 1 or ROMANA 2 trials (0-12 weeks) could enroll in ROMANA 3 and continue to receive anamorelin 100 mg or placebo once daily for an additional 12w (12-24 weeks). The primary endpoint of ROMANA 3 was anamorelin safety/tolerability (12-24 weeks). Secondary endpoints included changes in body weight, handgrip strength (HGS), and symptom burden (0-24 weeks). Results: Of the 703 patients who completed ROMANA 1 and ROMANA 2, 513 patients entered ROMANA 3 (anamorelin, N = 345, mean age 62.0 years; placebo, N = 168; mean age 62.2 years). During ROMANA 3, anamorelin and placebo groups had similar incidences of treatment-emergent adverse events (TEAEs; 52.2% versus 55.7%), grade ≥ 3 TEAEs (22.4% versus 21.6%), and serious TEAEs (12.8% versus 12.6%). There were 36 (10.5%) and 23 (13.8%) deaths in the anamorelin and placebo groups, respectively; none were drug-related. Improvements in body weight and anorexia-cachexia symptoms observed in the original trials were consistently maintained over 12-24 weeks. Anamorelin, versus placebo, significantly increased body weight from baseline of original trials at all time points (P < 0.0001) and improved anorexia-cachexia symptoms at weeks 3, 6, 9, 12, and 16 (P < 0.05). No significant improvement in HGS was seen in either group. Conclusion: During the 12-24 weeks ROMANA 3 trial, anamorelin continued to be well tolerated. Over the entire 0-24w treatment period, body weight and symptom burden were improved with anamorelin
Cell cycle arrest and induction of apoptosis in pancreatic cancer cells exposed to eicosapentaenoic acid in vitro.
Eicosapentaenoic acid (EPA) has been shown to have an inhibitory effect on the growth of several pancreatic cancer cell lines in vitro. This study investigates the mechanism of growth inhibition and cytotoxicity of EPA on the pancreatic cancer cell line MIA PaCa-2. Cells were analysed for cell count, viability, cell cycle distribution and ultrastructural changes. There was a time- and dose-dependent decrease in cell count and viability in cultures of pancreatic cancer cells supplemented with EPA. Flow cytometric DNA analysis of MIA PaCa-2 cells incubated with EPA demonstrated the presence of sub G1 populations corresponding to the presence of apoptotic cells and the blockade of cell cycle progression in S-phase and G2/M-phase. The presence of apoptosis in EPA-supplemented cultures was further confirmed by DNA fragmentation and ultrastructural changes associated with apoptosis. Therefore, we conclude that EPA mediates its effect on the pancreatic cancer cell line MIA PaCa-2, at least in part, via cell cycle arrest and the induction of apoptosis
Revision of failed traditional fundoplication using EsophyX® transoral fundoplication
BACKGROUND: Laparoscopic revision of failed traditional fundoplication is difficult and involves risk of gastric, esophageal, and vagal nerve injury that is higher than that of the primary fundoplication. This study assessed feasibility and clinical outcomes of the transoral approach to revision of loose Nissen. METHODS: Between November 2009 and August 2011, a total of 11 patients underwent transoral repair as opposed to 70 patients who underwent laparoscopic or open revision of a failed fundoplication. Subjective and objective outcomes were evaluated with the GERD health-related quality of life (GERD-HRQL) questionnaire and the reflux symptom index (RSI) questionnaire and ambulatory pH testing. The competency of the new antireflux barrier was evaluated by endoscopy. Wilcoxon signed-rank test was used to compare pre- and postoperative variables. RESULTS: All 11 patients evidenced loosening of the Nissen fundoplication without evidence of hiatal failure. Mean age was 57 years, BMI was 25.1 kg/m(2), and 4 of 11 (36 %) were female. Indications for operation were abnormal pH-metry off PPIs (6), impedance/pH on PPIs (3), esophagitis (1), and evidence of free reflux on barium swallow (1). One patient developed a postoperative bleed requiring transfusion. Two patients had laparoscopic revision at 6 and 8 months after the transoral procedure. At a median follow-up of 14 (range = 6–28) months, 8/10 patients reported resolution of their primary symptoms. Eight patients had pH testing off PPIs both pre- and postoperatively; median % time with pH <4 improved by dropping from 8.1 % (21–4.8 %) to 0.6 % (13.4–0.01 %) (p = 0.008). Esophageal acid exposure normalized in 5/6 patients. Mean GERD-HRQL score improved significantly by dropping from 28.6 (10.6) preoperatively to 6.7 (6.1) post-TIF (p = 0.016). Mean RSI score improved more than 50 % in 5/7 patients. CONCLUSION: Transoral revision of failed traditional fundoplication without herniation is technically feasible. It results in symptomatic and objective improvement of GERD without the risks of laparoscopic dissection for a majority of patients
A polymorphism of the interleukin-1 β gene influences survival in pancreatic cancer
Pro-inflammatory cytokines contribute to the cachexia associated with pancreatic cancer and stimulate the acute phase response which has been associated with shortened survival in such patients. Polymorphisms of cytokine genes may influence their production. The present study examined the effect of a polymorphism of the interleukin (IL)-1b gene upon the inflammatory state and survival in pancreatic cancer. Genomic DNA was obtained from 64 patients with pancreatic cancer and 101 healthy controls. Using the polymerase chain reaction and subsequent TaqI restriction enzyme digestion the subject's genotype for a diallelic polymorphism of the interleukin-1b gene was established. IL-1b production by peripheral blood mononuclear cells and serum C-reactive protein (CRP) levels from patients were also examined and survival noted. Patients homozygous for allele 2 of the IL-1b gene had significantly shorter survival than other groups (P = 0.0001). These patients also exhibited higher IL-1b production (P = 0.022). Possession of allele 2 was also associated with significantly shorter survival (median 144 vs 256 days, P = 0.034) and significantly higher CRP level (P = 0.0003). The possession of a genotype resulting in increased IL-1b production was associated with shortened survival and increased serum CRP level. This may reflect the role of IL-1b in inducing an acute phase protein response and cachexia in cancer or may be related to changes in tumour phenotye. © 2000 Cancer Research Campaign http://www.bjcancer.co
Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines.
A number of polyunsaturated fatty acids have been shown to inhibit the growth of malignant cells in vitro. To investigate whether fatty acids modify the growth of human pancreatic cancer, lauric, stearic, palmitic, oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic and eicosapentaenoic (EPA) acids were each incubated with the cells lines MIA PaCa-2, PANC-1 and CFPAC at concentrations ranging from 1.25 microM to 50 microM and the effect of each fatty acid on cell growth was examined. All the polyunsaturated fatty acids tested had an inhibitory effect, with EPA being the most potent (ID50 2.5-5 microM). Monounsaturated or saturated fatty acids were not inhibitory. The action of EPA could be reversed with the anti-oxidant vitamin E acetate or with oleic acid. The cyclo-oxygenase inhibitors indomethacin and piroxicam had no effect on the action of EPA. The action of EPA appeared to be associated with the generation of lipid peroxides, although the level of lipid peroxidation did not always appear to correlate directly with the extent of cell death. The ability of certain fatty acids to inhibit significantly the growth of three human pancreatic cancer cell lines in vitro at concentrations which could be achieved in vivo suggests that administration of such fatty acids may be of therapeutic benefit in patients with pancreatic cancer
Ibuprofen reduces energy expenditure and acute-phase protein production compared with placebo in pancreatic cancer patients.
The aim of this study was to investigate the effect of the cyclo-oxygenase inhibitor ibuprofen on the acute-phase protein response and resting energy expenditure (REE) of weight-losing patients with pancreatic cancer. Patients with irresectable pancreatic cancer (n = 16) were treated with either ibuprofen (1200 mg day-1 for 7 days (n = 10) or placebo (n = 6). A group of 17 age-related non-cancer subjects were also studied. Indirect calorimetry, anthropometry, multifrequency bioelectrical impedence analysis and serum C-reactive protein (CRP) estimation were performed immediately before and after treatment. Before treatment, total REE was significantly elevated in the pancreatic cancer patients compared with healthy controls (1499 +/- 71 vs 1377 +/- 58 kcal) (P < 0.02). Following treatment the mean REE of the ibuprofen group fell significantly (1386 +/- 89 kcal) compared with pretreatment values (1468 +/- 99 kcal) (P < 0.02), whereas no change was observed in the placebo group. Serum CRP concentration was also reduced in the ibuprofen-treated group (pre-ibuprofen, 51 mg l-1; post-ibuprofen, 29 mg l-1; P < 0.05). These results suggest that ibuprofen may have a role in abrogating the catabolic processes which contribute to weight loss in patients with pancreatic cancer
In Vivo Fluorescence-Based Endoscopic Detection of Colon Dysplasia in the Mouse Using a Novel Peptide Probe
Colorectal cancer (CRC) is a major cause of cancer-related deaths in much of the
world. Most CRCs arise from pre-malignant (dysplastic) lesions, such as
adenomatous polyps, and current endoscopic screening approaches with white light
do not detect all dysplastic lesions. Thus, new strategies to identify such
lesions, including non-polypoid lesions, are needed. We aim to identify and
validate novel peptides that specifically target dysplastic colonic epithelium
in vivo. We used phage display to identify a novel peptide
that binds to dysplastic colonic mucosa in vivo in a
genetically engineered mouse model of colo-rectal tumorigenesis, based on
somatic Apc (adenomatous polyposis coli) gene
inactivation. Binding was confirmed using confocal microscopy on biopsied
adenomas and excised adenomas incubated with peptide ex vivo.
Studies of mice where a mutant Kras allele was somatically
activated in the colon to generate hyperplastic epithelium were also performed
for comparison. Several rounds of in vivo T7 library biopanning
isolated a peptide, QPIHPNNM.
The fluorescent-labeled peptide bound to dysplastic lesions on endoscopic
analysis. Quantitative assessment revealed the fluorescent-labeled peptide
(target/background: 2.17±0.61) binds ∼2-fold greater to the colonic
adenomas when compared to the control peptide (target/background:
1.14±0.15), p<0.01. The peptide did not bind to the non-dysplastic
(hyperplastic) epithelium of the Kras mice. This work is first
to image fluorescence-labeled peptide binding in vivo that is
specific towards colonic dysplasia on wide-area surveillance. This finding
highlights an innovative strategy for targeted detection to localize
pre-malignant lesions that can be generalized to the epithelium of hollow
organs
The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer
At baseline, weight-losing pancreatic cancer patients (n=7) had lower leptin (P<0.05) but higher cortisol, interleukin-6, resting energy expenditure and fat oxidation than healthy subjects (n=6, P<0.05). Over a 4 h feeding period, the areas under the curve for glucose, cortisol and interleukin-6 were greater (P<0.05), but less for leptin in the cancer group (P<0.05). Therefore, it would appear that low leptin concentrations, increased fat oxidation and insulin resistance are associated with increased concentrations of cortisol and interleukin-6 in weight-losing patients with pancreatic cancer
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