Randomised study of adjuvant chemotherapy for completely resected p-stage I–IIIA non-small cell lung cancer

We evaluated the therapeutic usefulness of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). We also examined the relation between DNA ploidy pattern and the response to chemotherapy. A total of 267 patients with NSCLC (pathologically documented stage I, II, or IIIA) underwent complete resection, and DNA ploidy pattern was analysed. Patients with stage I disease (n=172) were randomly assigned to receive surgery alone (group A) or surgery followed by adjuvant chemotherapy (UFT (oral anti-cancer drug, a combination of Uracil and Tegaful) 400 mg day−1 for 1 year after surgery; group B). Stage II or IIIA disease patients (n=95) were randomly assigned to surgery alone (group C) or surgery followed by chemotherapy (two 28-day courses of cisplatin 80 mg m−2 on day 1 plus vindesine 3 mg m−2 on days 1 and 8, followed by UFT 400 mg day−1 for at least 1 year; group D). Eight-year overall survival rate in patients with stage I disease was 74.2% (95% confidence interval (CI): 64.4–84.0%) in group B and 57.6% (95% CI: 46.4–68.8%) in group A (P=0.045 by log-rank test). In patients with stage II and IIIA disease, no difference was found between groups C and D. Analysis according to DNA ploidy pattern revealed no difference between the groups. Postoperative chemotherapy with UFT was suggested to be useful in patients with completely resected stage I NSCLC. No difference was seen in relation to DNA pattern in any treatment group

Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients

Background: Primary ciliary dyskinesia (PCD) is a relatively rare autosomal recessive or X-linked disorder affecting ciliary function. In the set of causative genes, however, predominant pathogenic variants remain unknown in Asia. Method: A diagnosis of PCD was made following a modern comprehensive testing including genetic analysis; targeted resequencing for screening variants, and Sanger sequencing for determination of the breakpoints, with an additional review of databases to calculate the deletion frequency. A multiplexed PCR-based detection method has also been developed. Results: We ascertained a 50-year-old Japanese male who had been diagnosed with diffuse panbronchiolitis (DPB), but refractory to macrolide therapy. We reevaluated the case and identified a large homozygous deletion spanning exons 1 to 4 of the DRC1 and determined the breakpoints (NM_145038.4: c.1-3952_540 + 1331del27748-bp). In the PCD cohort at the University of North Carolina, we found a female PCD patient of Korean descent harboring the same homozygous deletion. From the Invitae testing cohort, we extracted four carriers of the same deletion among 965 Asian individuals, whereas no deletion was found in the 23,951 non-Asians. Conclusion: We speculate that the DRC1 deletion is a recurrent or perhaps founder mutation in Asians. The simple PCR method could be a useful screening tool

A phase I study of combination chemotherapy with gemcitabine and oral UFT for advanced non-small cell lung cancer

A phase I study was carried out to determine the optimal dose and administration schedule for combined UFT plus gemcitabine therapy in patients with non-small cell lung cancer. Twenty-four patients (including 11 patients previously treated with cisplatin as the key drug) received oral UFT 400 mg m−2 on days 1 to 14 with intravenous infusions of gemcitabine (800 mg m−2 on days 8 and 15, or 900 mg m−2 on days 8 and 15, or 900 mg m−2 on days 1, 8 and 15). The most appropriate dosing option appeared to be 400 mg m−2 per day of oral UFT for 14 consecutive days with 900 mg m−2 gemcitabine on days 8 and 15. Eight of the 24 patients achieved partial response. The combination chemotherapy UFT and gemcitabine was well tolerated and may benefit patients with advanced non-small cell lung cancer. A multicentre phase II study using a 3-weekly regimen is in progress

Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m−2day−1: BSA < 1.25 m2, 40 mg b.i.d.; BSA≥1.25 but <1.5 m2; 50 mg b.i.d., and BSA≥1.5 m2: 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3–34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1–13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7–14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Association of IFNGR2 gene polymorphisms with pulmonary tuberculosis among the Vietnamese

Interferon-γ (IFN-γ) is a key molecule of T helper 1 (Th1)-immune response against tuberculosis (TB), and rare genetic defects of IFN-γ receptors cause disseminated mycobacterial infection. The aim of the present study was to investigate whether genetic polymorphisms found in the Th1-immune response genes play a role in TB. In our study, DNA samples were collected from two series of cases including 832 patients with new smear-positive TB and 506 unrelated individuals with no history of TB in the general population of Hanoi, Vietnam. Alleles of eight microsatellite markers located around Th1-immune response-related genes and single nucleotide polymorphisms near the promising microsatellites were genotyped. A set of polymorphisms within the interferon gamma receptor 2 gene (IFNGR2) showed a significant association with protection against TB (P = 0.00054). Resistant alleles tend to be less frequently found in younger age at diagnosis (P = 0.011). Luciferase assays revealed high transcriptional activity of the promoter segment in linkage disequilibrium with resistant alleles. We conclude that the polymorphisms of IFNGR2 may confer resistance to the TB development of newly infected individuals. Contribution of the genetic factors to TB appeared to be different depending on age at diagnosis

Circulating Levels of Adiponectin, Leptin, Fetuin-A and Retinol-Binding Protein in Patients with Tuberculosis: Markers of Metabolism and Inflammation

BACKGROUND: Wasting is known as a prominent feature of tuberculosis (TB). To monitor the disease state, markers of metabolism and inflammation are potentially useful. We thus analyzed two major adipokines, adiponectin and leptin, and two other metabolic markers, fetuin-A and retinol-binding protein 4 (RBP4). METHODS: The plasma levels of these markers were measured using enzyme-linked immunosorbent assays in 84 apparently healthy individuals (=no-symptom group) and 46 patients with active pulmonary TB around the time of treatment, including at the midpoint evaluation (=active-disease group) and compared them with body mass index (BMI), C-reactive protein (CRP), chest radiographs and TB-antigen specific response by interferon-γ release assay (IGRA). RESULTS: In the no-symptom group, adiponectin and leptin showed negative and positive correlation with BMI respectively. In the active-disease group, at the time of diagnosis, leptin, fetuin-A and RBP4 levels were lower than in the no-symptom group [adjusted means 2.01 versus 4.50 ng/ml, P<0.0001; 185.58 versus 252.27 µg/ml, P<0.0001; 23.88 versus 43.79 µg/ml, P<0.0001, respectively]. High adiponectin and low leptin levels were associated with large infiltrates on chest radiographs even after adjustment for BMI and other covariates (P=0.0033 and P=0.0020). During treatment, adiponectin levels increased further and then decreased. Leptin levels remained low. Initial low levels of fetuin-A and RBP4 almost returned to the normal reference range in concert with reduced CRP. CONCLUSIONS: Our data and recent literature suggest that low fat store and underlying inflammation may regulate these metabolic markers in TB in a different way. Decreased leptin, increased adiponectin, or this ratio may be a promising marker for severity of the disease independent of BMI. We should further investigate pathological roles of the balance between these adipokines

Respiratory epithelial cells require Toll-like receptor 4 for induction of Human β-defensin 2 by Lipopolysaccharide

BACKGROUND: The respiratory epithelium is a major portal of entry for pathogens and employs innate defense mechanisms to prevent colonization and infection. Induced expression of human β-defensin 2 (HBD2) represents a direct response by the epithelium to potential infection. Here we provide evidence for the critical role of Toll-like receptor 4 (TLR4) in lipopolysaccharide (LPS)-induced HBD2 expression by human A549 epithelial cells. METHODS: Using RTPCR, fluorescence microscopy, ELISA and luciferase reporter gene assays we quantified interleukin-8, TLR4 and HBD2 expression in unstimulated or agonist-treated A549 and/or HEK293 cells. We also assessed the effect of over expressing wild type and/or mutant TLR4, MyD88 and/or Mal transgenes on LPS-induced HBD2 expression in these cells. RESULTS: We demonstrate that A549 cells express TLR4 on their surface and respond directly to Pseudomonas LPS with increased HBD2 gene and protein expression. These effects are blocked by a TLR4 neutralizing antibody or functionally inactive TLR4, MyD88 and/or Mal transgenes. We further implicate TLR4 in LPS-induced HBD2 production by demonstrating HBD2 expression in LPS non-responsive HEK293 cells transfected with a TLR4 expression plasmid. CONCLUSION: This data defines an additional role for TLR4 in the host defense in the lung

Models of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem and is predicted to become the third most common cause of death by 2020. Apart from the important preventive steps of smoking cessation, there are no other specific treatments for COPD that are as effective in reversing the condition, and therefore there is a need to understand the pathophysiological mechanisms that could lead to new therapeutic strategies. The development of experimental models will help to dissect these mechanisms at the cellular and molecular level. COPD is a disease characterized by progressive airflow obstruction of the peripheral airways, associated with lung inflammation, emphysema and mucus hypersecretion. Different approaches to mimic COPD have been developed but are limited in comparison to models of allergic asthma. COPD models usually do not mimic the major features of human COPD and are commonly based on the induction of COPD-like lesions in the lungs and airways using noxious inhalants such as tobacco smoke, nitrogen dioxide, or sulfur dioxide. Depending on the duration and intensity of exposure, these noxious stimuli induce signs of chronic inflammation and airway remodelling. Emphysema can be achieved by combining such exposure with instillation of tissue-degrading enzymes. Other approaches are based on genetically-targeted mice which develop COPD-like lesions with emphysema, and such mice provide deep insights into pathophysiological mechanisms. Future approaches should aim to mimic irreversible airflow obstruction, associated with cough and sputum production, with the possibility of inducing exacerbations