pulmicort and Adenocarcinoma

EMR and endoscopic submucosal dissection (ESD) are treatment modalities for Barrett's esophagus involving high-grade dysplasia or early cancer. Injectional corticosteroid therapy decreases the risk of procedure-related esophageal stricture (ES) formation. Our aim was to assess the efficacy of topical budesonide on the rate of ES formation after EMR or ESD.. Patients included prospectively from 3 tertiary endoscopy centers received 3 mg budesonide orally twice a day for 8 weeks after esophageal EMR or ESD of 50% or more of the esophageal circumference between January 1, 2014 and June 30, 2018. These patients were matched (1:3 ratio) retrospectively with a consecutive patient cohort who underwent EMR or ESD of 50% or more of the esophageal circumference without concomitant corticosteroid therapy. The primary endpoint was the presence of ES at the 12-week follow-up.. Twenty-five patients (budesonide) were matched with 75 patients (no budesonide). Most underwent EMR for Barrett's esophagus with biopsy-proven high-grade dysplasia or suspected T1a cancer. Although most baseline characteristics did not differ significantly, patients in the budesonide cohort tended to have a higher proportion of circumferential EMR. The proportion of patients with ES was not significantly lower in the budesonide cohort (16% vs 28%). On logistic regression analysis, budesonide remained associated with a lower incidence of ES (P = .023); however, when controlling for baseline characteristics with a propensity score weighted logistic regression model, there was no significant effect on ES formation (P = .176).. Topical budesonide might be associated with a reduction of ES after EMR or ESD; however, further studies are needed to verify our results.

Topics: Adenocarcinoma; Barrett Esophagus; Budesonide; Endoscopic Mucosal Resection; Esophageal Neoplasms; Esophageal Stenosis; Humans; Retrospective Studies

Chemotherapy-induced diarrhoea (CID) is a risk of antineoplastic regimens, often associated with 5-fluorouracil (5-FU), irinotecan and capecitabine. Current treatment guidelines for CID include the use of loperamide and octreotide but do not account for other therapies, including budesonide. Small case reports have shown benefit with budesonide in CID secondary to 5-FU and irinotecan, but there is no literature base addressing budesonide use in CID secondary to capecitabine. We describe a case of a patient with severe capecitabine-induced diarrhoea that was refractory to guideline based therapy but resolved with the use of budesonide.

Topics: Adenocarcinoma; Aged, 80 and over; Antimetabolites, Antineoplastic; Budesonide; Capecitabine; Diarrhea; Female; Glucocorticoids; Humans; Rectal Neoplasms

Complete endoscopic resection (CER) of short-segment Barrett's esophagus with high grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a precise staging tool and achieves durable disease control. The major drawback is development of post-endoscopic resection esophageal stricture (PERES). No effective therapy to prevent PERES has been described. Viscous budesonide slurry (VBS) may have a role in the prevention of PERES by suppressing the post-CER inflammatory process. The study aim was to evaluate the efficacy of VBS for the prevention of PERES.. Prospective data were collected on patients referred for CER of HGD or EEA. After January 2012, patients routinely received VBS (two 0.5-mg/2-mL budesonide respules mixed with sucralose) twice daily for 6 weeks following each stage of the CER schedule. All patients received high dose proton pump inhibitor therapy for the duration of CER and the following 3 months. Patients had no other intervention to prevent PERES. A validated dysphagia score was used (0 - 4, no dysphagia to aphagia). Endoscopic dilation was performed for dysphagia. Patients receiving VBS were compared with historical controls. The primary endpoint was the need for dilation.. Between January 2008 and January 2015, 104 of 116 eligible patients completed CER. The VBS group (n = 29) and non-VBS group (n = 75) had similar patient, disease, and procedural characteristics. Dilations were needed in 13.8 % vs. 37.3 % (P = 0.03), with a median of one vs. two procedures (P = 0.01), and median dysphagia score during CER of 0 vs. 1 (P = 0.02) in the VBS and non-VBS groups, respectively. No VBS-related adverse events were noted.. In this pilot study VBS significantly reduced PERES and shortened the dilation program after CER.

Topics: Adenocarcinoma; Adult; Aged; Anti-Inflammatory Agents; Barrett Esophagus; Budesonide; Drug Administration Schedule; Esophageal Neoplasms; Esophageal Stenosis; Esophagoscopy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pilot Projects; Postoperative Complications; Precancerous Conditions; Prospective Studies; Treatment Outcome; Viscosity

A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT.. We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed.. The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms.. Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications.. NCT01540552.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Antineoplastic Agents; Budesonide; Clinical Trials, Phase II as Topic; Early Detection of Cancer; Humans; Lung Neoplasms; Multidetector Computed Tomography; Multiple Pulmonary Nodules; Precancerous Conditions; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Solitary Pulmonary Nodule; Time Factors; Treatment Outcome

Glucocorticoids (GCs) are well-known anti-inflammatory compounds, but they also inhibit cell proliferation depending on cell type. Similarly, peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ) also possess anti-proliferation properties beyond their canonical roles as metabolic mediators. In the present study, we investigated the potential additive or synergistic inhibitory effects on cancer cell proliferation by simultaneous application of fenofibrate and budesonide, agonists for PPARα and glucocorticoid receptor, respectively. We observed differential effects on cell proliferation in A549 and SK-MES-1 lung cancer cells by budesonide and fenofibrate. Fenofibrate inhibited cell proliferation in both TP53 wild type and deficient lung cancer cells. The anti-proliferation effect of budesonide in TP53 wild type A549 cells was abolished in SK-MES-1 cells that do not have wild type TP53 protein. An additive effect against cell proliferation by budesonide and fenofibrate combination was observed only in TP53 wild type A549 cancer cells. Analysis of cell cycle distribution and cyclin profile indicated that the inhibition of cell proliferation was associated with G1 cell cycle arrest. The suppression of NF-κB activity and ERK signaling may contribute to the inhibition of cell proliferation by budesonide and or fenofibrate. The additive inhibitory effect on cell proliferation by budesonide and fenofibrate combination suggests that the same or greater therapeutic effect could be achieved with reduced dosage and side effects when the two compounds are applied simultaneously.

Topics: Adenocarcinoma; Anti-Inflammatory Agents; Blotting, Western; Budesonide; Cell Cycle; Cell Proliferation; Fenofibrate; Flow Cytometry; Humans; Hypolipidemic Agents; Lung Neoplasms; NF-kappa B; PPAR alpha; Real-Time Polymerase Chain Reaction; Receptors, Glucocorticoid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Tumor Suppressor Protein p53

For locally acting drugs, an extended residence time in the nasal cavity is desirable and related to a prolonged effect. We sought to develop a model for comparative determination of intranasal pharmacokinetics. We embedded human respiratory tissue into a solid matrix and coated the surface with artificial nasal fluid. Nasal spray suspensions of fluticasone propionate (FP) and budesonide (Bud) as well as a solution of azelastine hydrochloride (AZ) were applied onto the surface and removed after 30 min to simulate mucociliary clearance. As exemplary anti-inflammatory measure, we evaluated the inhibition of IL-8 release from epithelial cells. FP and Bud were initially bound to the same extent to the tissue gel while AZ displayed a more 4-fold higher binding than FP or Bud. After equilibrium with plasma, approximately 5-fold higher tissue concentrations of AZ compared to FP and 77-fold higher levels in relation to Bud were determined. This tissue retention revealed an excellent correlation with the volume of distribution of the respective drugs (r=0.9999, p ≤ 0.05). The inhibitory effect of FP on IL-8 release was approximately 5-fold more pronounced compared to AZ. The present model realistically mirrors conditions in vivo where solubility and tissue absorption of intranasally applied drugs compete with mucociliary clearance mechanisms.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Administration, Inhalation; Administration, Intranasal; Aerosols; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Budesonide; Cell Line, Tumor; Delayed-Action Preparations; Epithelial Cells; Fluticasone; Glucocorticoids; Histamine Antagonists; Humans; Interleukin-8; Lung; Lung Neoplasms; Mucociliary Clearance; Nasal Lavage Fluid; Nasal Sprays; Phthalazines; Rhinitis, Allergic, Seasonal

p53 transgenic mice carrying a dominant negative mutation were crossed with Ink4A/Arf heterozygous-deficient mice to investigate whether there is a synergy between these two germ-line mutations in promoting carcinogen-induced lung tumor progression in mice. Mice with a p53 dominant negative mutation and Ink4A/Arf heterozygous deficiency exhibited >20-fold increase in tumor volume compared with approximately 4-fold increase in Ink4A/Arf heterozygous-deficient mice and a 9-fold increase in mice with only the p53 dominant negative mutation. The effect of Ink4A/Arf heterozygous deficiency on lung tumor progression occurred late in the carcinogenesis process (>30 weeks after carcinogen treatment). In addition, most of the lung tumors (approximately 80%) from mice with a p53 mutation and deletion of Ink4A/Arf were lung adenocarcinomas. In contrast, lung adenocarcinomas were seen in <10% of the lung tumors from the wild-type mice and approximately 50% of the lung tumors from Ink4a/Arf heterozygous-deficient or p53 mutant mice. These results indicate a significant synergistic interaction between the presence of a mutant p53 transgene and the Ink4A/Arf deletion during lung tumor progression (P < 0.01). The usefulness of this new mouse model in lung cancer chemoprevention was examined. The chemopreventive efficacy of budesonide was examined in wild-type mice, mice with Ink4A/Arf heterozygous deficiency, mice with a mutation in the p53 gene, or mice with both a mutation in the p53 gene and deletion in the Ink4A/Arf locus. Mice treated with budesonide displayed an average of 90% inhibition of lung tumor progression in a standard 18-week chemoprevention assay, regardless of p53 and/or Ink4A/Arf status. However, the efficacy of budesonide against lung tumor progression decreased from 94 to 77% (P = 0.07) in mice with alterations in both p53 and Ink4A/Arf in a 40-week chemoprevention assay. Similarly, when mice bearing established lung adenomas were treated with budesonide, genotype-dependent differential effects of budesonide in wild-type and mutant mice were clearly revealed with a 82, 64, 45, and 33% decrease in tumor volume in wild-type mice, p53(+/+)Ink4a/Arf(+/-) mice, p53(+/-)Ink4a/Arf(+/+) mice, and p53(+/-)Ink4a/Arf(+/-), respectively. Thus, mutant mice with alterations in p53 and/or Ink4A/Arf exhibited a significant resistance to chemoprevention by budesonide. Because p53 and Ink4a/Arf mutations are the most prevalent mutations in human lung cancers, the effec

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Budesonide; Carcinogens; Cyclin-Dependent Kinase Inhibitor p16; Disease Progression; Female; Genes, p53; Genetic Predisposition to Disease; Germ-Line Mutation; Inbreeding; Lung Neoplasms; Male; Mice; Mice, Inbred A; Mice, Transgenic

Chemopreventive drugs have the potential to decrease the morbidity and mortality of lung cancer. The development of these drugs could be expedited by the application of surrogate end-point biomarkers that demonstrate chemopreventive efficacy. In this study, the ability of budesonide to prevent lung tumors in mice was characterized further and its effects on biomarkers were determined. Lung tumors were induced in female strain A mice by vinyl carbamate (16 mg/kg) administered once weekly for 2 consecutive weeks. Four weeks later the mice started to receive 0.6, 1.2 or 2.4 mg/kg budesonide continually in the diet until killed at week 20. Budesonide caused a dose-dependent decrease in the multiplicity of lung tumors of 25, 58 and 82%, respectively. Budesonide (2.4 mg/kg diet) administered starting at weeks 4, 10 or 16, decreased tumor multiplicity by 82, 66 and 30% at week 20. Administering 2.4 mg/kg budesonide at weeks 4-20 or 20-35 and killing the mice at week 35 did not significantly decrease the yield of tumors, although both treatment regimens did decrease the size of the tumors and the progression of adenomas to carcinomas. Thus, budesonide delayed the appearance of lung tumors and decreased their growth and progression to carcinomas. To determine the effect of limited exposure to budesonide on biomarkers, it was administered for only 7 days prior to death at week 35. Budesonide decreased the proliferating cell nuclear antigen labeling in lung adenomas, carcinomas, parenchyma and bronchial airways by 87.6, 59.0, 41.1 and 25.4%, respectively. Budesonide treatment also increased the protein level of the p21 and p27 genes and increased the mRNA level of p21. Thus, short-term treatment with budesonide modulated biological and molecular end-points in lung tumors that might be developed further as biomarkers for its clinical chemopreventive efficacy in the lung.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Biomarkers, Tumor; Budesonide; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; DNA Primers; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Mice; Mice, Inbred A; Microfilament Proteins; Muscle Proteins; Polymerase Chain Reaction; RNA, Messenger; Urethane

The use of surrogate end-point biomarkers could help in the development of chemopreventive agents. To define potential surrogate end-point biomarkers, the ability of budesonide to decrease mRNA expression of the insulin-like growth factor-2 (Igf-II) and c-myc genes and to cause the remethylation of the genes was investigated in lung tumors. Lung tumors were induced in female strain A mice by administering i.p. 16 mg/kg vinyl carbamate for 2 consecutive wk or by a single dose of 100 mg/kg benzo[a]pyrene (B[a]P). Thirty-four weeks later, the mice given vinyl carbamate received budesonide (0.6 or 2.4 mg/kg diet) for 7 d and then were killed. Mice were killed 24 wk after administration of B[a]P. The mRNA expression of the Igf-II and c-myc genes was increased in lung tumors relative to normal lung tissue. Budesonide decreased mRNA expression of both genes in tumors. The methylation status of 27 CpG sites in the differentially methylated region 2 in the Igf-II gene was determined with the bisulfite-treated DNA-sequencing procedure. The numbers of methylated CpG sites were 17-21 in normal lung (70.4 +/- 2.6%); 0-2, and 1-2 in lung tumors induced by vinyl carbamate and B[a]P (4.9 +/- 1.2% and 4.6 +/- 1.2%, respectively); and 4-5 or 7-16 in tumors after treatment with 0.6 or 2.4 mg/kg budesonide (16.0 +/- 1.2% and 46.2 +/- 5.1%, respectively). Thus, lung tumors had strikingly less methylated CpG sites than normal lung tissue, while even limited treatment with budesonide resulted in remethylation of the CpG sites in tumors. With HpaII digestion followed by Southern blot analysis, the internal cytosine of CCGG sites in the c-myc gene was found to be methylated in normal lung tissue, whereas some of the sites were unmethylated in lung tumors. Treatment for 7 d with budesonide resulted in the remethylation of these sites. In conclusion, mouse lung tumors showed decreased methylation of the Igf-II and c-myc genes that was associated with increased expression of these genes. Budesonide treatment caused remethylation and decreased expression of both genes. The results support the possibility of using decreased mRNA expression and remethylation of the Igf-II and c-myc genes as biomarkers for the efficacy of budesonide.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Budesonide; CpG Islands; DNA Methylation; DNA Primers; DNA, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Insulin-Like Growth Factor II; Lung Neoplasms; Mice; Mice, Inbred A; Proto-Oncogene Proteins c-myc; RNA, Messenger; RNA, Neoplasm

The transcription factor Fos is involved in cell proliferation and differentiation. Its expression in normal and pathological adult human tissues and cells has rarely been studied. We therefore studied bronchial biopsies obtained from 14 normal subjects (NS), 18 non-steroid-treated asthmatics, 10 corticosteroid-treated asthmatics and 10 patients with chronic bronchitis (CB), in addition to 34 patients with lung cancer (LC), by immunofluorescence for Fos immunoreactivity, using a highly specific polyclonal antibody. Bronchial tissue of 0/10 NS, 11/18 non-steroid-treated asthmatics, 1/10 steroid-treated asthmatics, 0/10 CB and 1/34 LC expressed Fos. In asthmatic patients, the expression was heterogeneous, localized to epithelial cells and correlated with the epithelium shedding (tau = 0.45, P = 0.0001). Corticosteroid-treated patients rarely expressed Fos, suggesting a role for this proto-oncogene in asthmatic bronchial inflammation. Fos was rarely expressed in the normal and pathological (CB, LC) proliferative compartment of the human bronchi, suggesting its low role in cell proliferation of the large airways.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Beclomethasone; Bronchi; Bronchitis; Budesonide; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chronic Disease; Female; Fluorescent Antibody Technique; Humans; Lung Neoplasms; Male; Middle Aged; Pregnenediones; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos