ORCID Profile
0000-0002-6507-1403
Current Organisation
Prince Charles Hospital
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Publisher: Wiley
Date: 19-04-2012
DOI: 10.1111/J.1440-1843.2012.02164.X
Abstract: Adverse health effects from air pollutants remain important, despite improvement in air quality in the past few decades. The exact mechanisms of lung injury from exposure to air pollutants are not yet fully understood. Studying the genome (e.g. single-nucleotide polymorphisms (SNP) ), epigenome (e.g. methylation of genes), transcriptome (mRNA expression) and microRNAome (microRNA expression) has the potential to improve our understanding of the adverse effects of air pollutants. Genome-wide association studies of SNP have detected SNP associated with respiratory phenotypes however, to date, only candidate gene studies of air pollution exposure have been performed. Changes in epigenetic processes, such DNA methylation that leads to gene silencing without altering the DNA sequence, occur with air pollutant exposure, especially global and gene-specific methylation changes. Respiratory cell line and animal models demonstrate distinct gene expression signatures in the transcriptome, arising from exposure to particulate matter or ozone. Particulate matter and other environmental toxins alter expression of microRNA, which are short non-coding RNA that regulate gene expression. While it is clearly important to contain rising levels of air pollution, strategies also need to be developed to minimize the damaging effects of air pollutant exposure on the lung, especially for patients with chronic lung disease and for people at risk of future lung disease. Careful study of genomic responses will improve our understanding of mechanisms of lung injury from air pollution and enable future clinical testing of interventions against the toxic effects of air pollutants.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.JTHO.2018.02.012
Abstract: Over the past two decades, the International Association for the Study of Lung Cancer (IASLC) Staging Project has been a steady source of evidence-based recommendations for the TNM classification for lung cancer published by the Union for International Cancer Control and the American Joint Committee on Cancer. The Staging and Prognostic Factors Committee of the IASLC is now issuing a call for participation in the next phase of the project, which is designed to inform the ninth edition of the TNM classification for lung cancer. Following the case recruitment model for the eighth edition database, volunteer site participants are asked to submit data on patients whose lung cancer was diagnosed between January 1, 2011, and December 31, 2019, to the project by means of a secure, electronic data capture system provided by Cancer Research And Biostatistics in Seattle, Washington. Alternatively, participants may transfer existing data sets. The continued success of the IASLC Staging Project in achieving its objectives will depend on the extent of international participation, the degree to which cases are entered directly into the electronic data capture system, and how closely externally submitted cases conform to the data elements for the project.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2005
Abstract: TSLC1 (tumor suppressor in lung cancer-1, IGSF4) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell-cell adhesion. TSLC1 is connected to the actin cytoskeleton by DAL-1 (differentially expressed in adenocarcinoma of the lung-1, EPB41L3) and it directly associates with MPP3, one of the human homologues of a Drosophila tumor suppressor gene, Discs large. Recent data suggest that aberrant promoter methylation is important for TSLC1 inactivation in lung carcinomas. However, little is known about the other two genes in this cascade, DAL-1 and MPP3. Thus, we investigated the expression and methylation patterns of these genes in lung cancer cell lines, primary lung carcinomas and nonmalignant lung tissue s les. By reverse transcription-polymerase chain reaction, loss of TSLC1 expression was observed in seven of 16 (44%) non-small-cell lung cancer (NSCLC) cell lines and in one of 11 (9%) small-cell lung cancer (SCLC) cell lines, while loss of DAL-1 expression was seen in 14 of 16 (87%) NSCLC cell lines and in four of 11 (36%) SCLC cell lines. By contrast, MPP3 expression was found in all tumor cell lines analysed. Similar results were obtained by microarray analysis. TSLC1 methylation was seen in 13 of 39 (33%) NSCLC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs. DAL-1 methylation was observed in 17 of 39 (44%) NSCLC cell lines, in three of 11 (27%) SCLC cell lines and in 147 of 268 (55%) primary NSCLCs. In tumors of NSCLC patients with stage II-III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease. A significant correlation between loss of expression and methylation of the genes in lung cancer cell lines was found. Overall, 65% of primary NSCLCs had either TSLC1 or DAL-1 methylated. Methylation of one of these genes was detected in 59% of NSCLC cell lines however, in SCLC cell lines, methylation was much less frequently observed. The majority of nonmalignant lung tissue s les was not TSLC1 or DAL-1 methylated. Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2'-deoxycytidine. Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1016/J.LUNGCAN.2008.01.008
Abstract: In several countries, clinical practice guidelines for lung cancer recommend that multidisciplinary (MD) teams should be used to plan the management of all lung cancer patients. We conducted a systematic review to evaluate and critically appraise the effectiveness of multidisciplinary teams for lung cancer. Medline searches were carried out for the period 1984 to July 2007. We included any study that mentioned team working among specialists with diagnostic and curative therapeutic intent, where members of the team met at a specified time, either in person or by video or teleconferencing, to discuss the diagnosis and management of patients with suspected lung cancer. All study designs were included. We were particularly interested in whether multidisciplinary working improved survival but also considered other outcomes such as practice patterns and waiting times. Sixteen studies met the criteria for inclusion. Statistical pooling was not possible due to clinical heterogeneity. Only two of the primary studies reported an improvement in survival. Both were before-and-after designs, providing weak evidence of a causal association. Evidence of the effect of MD teams was stronger for changing patient management than for affecting survival. Six of the studies reported an increase in the percentage of patients undergoing surgical resection or an increase in the percentage of patients undergoing chemotherapy or radiotherapy with curative intent. This systematic review shows limited evidence linking MD teams with improved lung cancer survival. This does not mean that MD teams do not improve survival, merely that currently available evidence of this is limited. It seems intuitively obvious that MD teams should improve outcomes for lung cancer patients, but there are difficulties in conducting randomised trials to show this. The best way forward would be prospective evaluation of the effectiveness of MD teams as they are implemented, paying particular attention to collecting data on potential confounders.
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1111/RESP.13531
Publisher: AME Publishing Company
Date: 06-2018
Publisher: Wiley
Date: 04-1998
DOI: 10.1002/(SICI)1098-2264(199804)21:4<308::AID-GCC4>3.0.CO;2-2
Abstract: Allelic loss is a hallmark of tumor suppressor gene (TSG) inactivation. We have allelotyped 29 paired lymphoblastoid and lung cancer cell lines derived from 11 patients with small cell (SCLC) and 18 patients with non-small cell lung carcinomas (NSCLC). Statistical analysis indicated that a threshold of 30% separated non-random allelic loss from the random genetic deletions of malignancy. We have identified non-random allelic loss at 42 of 54 (78%) specific chromosomal regions examined, with 22 regions (52%) common between the two major lung cancer histologic types. There were 3 regions (7%) with allelic loss specific for SCLC and 17 regions (41%) specific for NSCLC. Furthermore, there were significant differences in loss of heterozygosity (LOH) frequencies between NSCLC and SCLC at 13 regions on eight chromosome arms (3p, 5q, 6q, 9p, 10q, 11p, 13q, and 19p). Eight homozygous deletions were present in seven cell lines at four regions, 3p12, 3p14.2, 9p21, and 10q23-25. We have also identified novel sites of chromosomal deletions. In particular, there was frequent loss at 11p13 in SCLC and loss at 6p21.3 and 13q12.3 in NSCLC. In this study, we demonstrate that a) non-random allelic losses in lung cancer involve multiple regions b) some losses are common to both NSCLC and SCLC subtypes, whereas others are subtype specific c) there are genetic deletions at novel chromosomal regions and d) several homozygous deletions have been noted. Our studies demonstrate the usefulness of continuous cell lines for detailed allelotyping, for comparing genetic abnormalities between SCLC and NSCLC, and for identifying homozygous deletions.
Publisher: Wiley
Date: 02-2013
DOI: 10.1111/J.1445-5994.2012.02789.X
Abstract: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years smoking history ≥30 pack years, current or quit within 15 years forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.
Publisher: Wiley
Date: 02-1990
DOI: 10.1111/J.1445-5994.1990.TB00377.X
Abstract: We report on a case of a 26-year-old intravenous narcotic abuser with a primary cerebral mucormycotic abscess caused by Rhizopus oryzae. He was treated with a combination of intravenous and intraventricular hotericin B and surgical drainage with a successful outcome. There was no evidence that his infection was acquired by the rhinocerebral route, it seems likely that he injected himself with a contaminated batch of narcotic or hetamine. Mucormycosis presenting in this way has been described previously but this is only the second such case to survive. Early diagnosis and treatment is essential for a favourable outcome in this condition.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2006
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1111/J.1753-6405.2012.00850.X
Abstract: Accurate information on spread-of-disease at diagnosis would increase the usefulness of hospital-activity data for cancer research. This study evaluates the accuracy of codes recorded in hospital-activity data to assign spread-of-disease at diagnosis for non-small cell lung cancer (NSCLC). The reference (gold) standard was TNM stage as assigned at a multi-disciplinary meeting. To allow comparison with hospital-activity data, TNM stage was mapped to spread-of-disease (local, regional, distant). Sensitivity, specificity and positive-predictive values were stratified by whether the patient had surgery. Data from the reference standard and hospital-activity database were available for 2,184 patients. According to the reference standard, local disease was present for 57.0% of surgical patients and 12.6% of non-surgical patients at diagnosis. Hospital-activity data over-estimated patients with local disease (surgical: 71.9%, non-surgical: 48.5%). There was a corresponding underestimation of distant spread-of-disease: surgical (reference standard: 4.0%, hospital-activity data: 2.7%) non-surgical (reference standard: 45.9%, hospital-activity data: 36.8%). This meant that hospital-activity data had good sensitivity but poor specificity for local disease and poor sensitivity, but good specificity for metastatic disease. Secondary diagnosis codes in hospital activity data do not accurately capture spread-of-disease at diagnosis for patients with non-small cell lung cancer even when the clinical notes contain TNM clinical stage as documented at a multidisciplinary meeting. Changes are needed to coding rules, and the ICD codes themselves, to allow for coding of regional and distant spread without specification of the precise site.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier
Date: 2006
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2005
DOI: 10.1158/0008-5472.CAN-04-3617
Abstract: Gene expression profiling offers a promising new technique for the diagnosis and prognosis of cancer. We have applied this technology to build a clinically robust site of origin classifier with the ultimate aim of applying it to determine the origin of cancer of unknown primary (CUP). A single cDNA microarray platform was used to profile 229 primary and metastatic tumors representing 14 tumor types and multiple histologic subtypes. This data set was subsequently used for training and validation of a support vector machine (SVM) classifier, demonstrating 89% accuracy using a 13-class model. Further, we show the translation of a five-class classifier to a quantitative PCR–based platform. Selecting 79 optimal gene markers, we generated a quantitative-PCR low-density array, allowing the assay of both fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tissue. Data generated using both quantitative PCR and microarray were subsequently used to train and validate a cross-platform SVM model with high prediction accuracy. Finally, we applied our SVM classifiers to 13 cases of CUP. We show that the microarray SVM classifier was capable of making high confidence predictions in 11 of 13 cases. These predictions were supported by comprehensive review of the patients' clinical histories.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Wiley
Date: 06-05-2014
DOI: 10.1111/RESP.12311
Abstract: Volume doubling time (VDT) contributes to the evaluation of the indeterminate pulmonary nodule, an increasingly frequent problem given the rising use of computed tomography (CT). We aimed to correlate patient and tumour characteristics with VDT and growth rates of primary non-small cell lung cancers (NSCLC). Surgically treated NSCLC, which underwent two or more CT scans separated by 25 or more days were studied. Tumour volume was measured using semi-automated volumetric software. VDT and growth rate (1/VDT) were correlated with patient and tumour characteristics. Thirty-six adenocarcinomas (AC), six squamous cell carcinoma (SCC), two large cell and two carcinoids in 46 patients had 109 eligible scans. Median VDT was 191 days (range -9435 to 2256 days) median growth rate was 0.0038 (range -0.0086 to 0.0186). Median growth rate of AC was significantly slower than SCC (0.0034 vs. 0.0103, P = 0.037). Nine AC had VDT >400 days, three of which developed distant metastases. Median growth rate of AC was faster in smokers compared with never-smokers (0.0052 vs. 0.0014, P = 0.02). Growth rate was not related to symptoms at diagnosis (P = 0.16). Less differentiated tumours tended to grow faster than more differentiated (P = 0.0038). Growth curves of 12 multi-imaged tumours conformed best with the exponential model of growth. NSCLC growth rate appears to be highly variable and related to histological subtype and smoking history, but not the presence of symptoms at diagnosis. Significant growth may be detected in as little as 2 months in NSCLC in smokers. Relatively slow-growing AC can metastasize.
Publisher: Springer Science and Business Media LLC
Date: 22-05-2003
Publisher: Wiley
Date: 26-11-2003
DOI: 10.1002/IJC.10787
Abstract: Aberrant methylation of several known or putative tumor suppressor genes occurs frequently during the pathogenesis of lung cancers. There are major smoke exposure, histology, geography and gender-related changes in non-small cell lung cancer (NSCLC). We investigated smoking-related, histologic, geographic and gender differences in the methylation profiles of resected NSCLCs. We examined 514 cases of NSCLC and 84 corresponding nonmalignant lung tissues from 4 countries (USA, Australia, Japan and Taiwan) for the methylation status of 7 genes known to be frequently methylated in lung cancers [p16, RASSF1A (RAS association domain family 1), APC, RARbeta, CDH13, MGMT and GSTP1]. Multivariate analyses were used for data analysis. Adenocarcinoma was the major histologic type in women and never smokers analyses that involved smoke exposure and gender were limited to this histology. Our major findings are a) methylation status of any single gene was largely independent of methylation status of other genes b) the rates of methylation of p16 and APC and the mean Methylation Index (MI), a reflection of the overall methylation status, were significantly higher in ever smokers than in never smokers c) the mean MI of tumors arising in former smokers was significantly lower than the mean of current smokers d) the methylation rates of APC, CDH13 and RARbeta were significantly higher in adenocarcinomas than in squamous cell carcinomas e) methylation rates of MGMT and GSTP1 were significantly higher in the USA and Australian cases than in those from Japan and Taiwan and (f) no significant gender-related differences in methylation patterns were noted. Our findings demonstrate important smoke exposure, histologic type and geography-related differences in the methylation profiles of NSCLC tumors.
Publisher: Springer Science and Business Media LLC
Date: 03-2000
Publisher: Elsevier
Date: 2006
Publisher: Elsevier BV
Date: 07-2020
Publisher: AME Publishing Company
Date: 10-2019
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 24-05-2006
DOI: 10.1111/J.1445-5994.2006.01074.X
Abstract: An important function of clinical cancer registries is to provide feedback to clinicians on various performance measures. To date, most clinical cancer registries in Australia are located in tertiary academic hospitals, where adherence to guidelines is probably already high. Microscopic confirmation is an important process measure for lung cancer care. We found that the proportion of patients with lung cancer without microscopic confirmation was much higher in regional public hospitals (27.1%) than in tertiary hospitals (7.5%), and this disparity remained after adjusting for age, sex and comorbidities. The percentage was also higher in the private than in the public sector. This case study shows that we need a population-based approach to measuring clinical indicators that includes regional public hospitals as a matter of priority and should ideally include the private sector.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JTHO.2017.04.011
Abstract: Revisions to the TNM stage classifications for lung cancer, informed by the international database (N = 94,708) of the International Association for the Study of Lung Cancer (IASLC) Staging and Prognostic Factors Committee, need external validation. The objective was to externally validate the revisions by using the National Cancer Data Base (NCDB) of the American College of Surgeons. Cases presenting from 2000 through 2012 were drawn from the NCDB and reclassified according to the eighth edition stage classification. Clinically and pathologically staged subsets of NSCLC were analyzed separately. The T, N, and overall TNM classifications were evaluated according to clinical, pathologic, and "best" stage (N = 780,294). Multivariate analyses were carried out to adjust for various confounding factors. A combined analysis of the NSCLC cases from both databases was performed to explore differences in overall survival prognosis between the two databases. The databases differed in terms of key factors related to data source. Survival was greater in the IASLC database for all stage categories. However, the eighth edition TNM stage classification system demonstrated consistent ability to discriminate TNM categories and stage groups for clinical and pathologic stage. The IASLC revisions made for the eighth edition of lung cancer staging are validated by this analysis of the NCDB database by the ordering, statistical differences, and homogeneity within stage groups and by the consistency within analyses of specific cohorts.
Publisher: Wiley
Date: 17-05-2022
DOI: 10.1111/RESP.14295
Publisher: Springer Science and Business Media LLC
Date: 09-07-0077
DOI: 10.1038/NATURE13385
Publisher: Wiley
Date: 11-2010
DOI: 10.1111/J.1445-5994.2009.02067.X
Abstract: To determine whether in-hospital deaths of patients admitted through emergency departments with acute exacerbations of chronic obstructive pulmonary disease (COPD), acute myocardial infarction, intracerebral haemorrhage and acute hip fracture are increased by weekend versus weekday admission (the 'weekend effect'). We performed a retrospective analysis of statewide administrative data from public hospitals in Queensland, Australia, during the 2002/2003-2006/2007 financial years. The primary outcome was 30-day in-hospital mortality. The secondary outcome of 2-day in-hospital mortality helped determine whether increased mortality of weekend admissions was closely linked to weekend medical care. During the study period, there were 30 522 COPD, 17 910 acute myocardial infarction, 4183 acute hip fracture and 1781 intracerebral haemorrhage admissions. There was no significant weekend effect on 30-day in-hospital mortality for COPD (adjusted risk ratio = 0.92, 95% CI: 0.81-1.04, P= 0.222), intracerebral haemorrhage (adjusted risk ratio = 1.01, 95% CI: 0.86-1.16, P= 0.935) or acute hip fracture (adjusted risk ratio = 0.78, 95% CI: 0.54-1.03, P= 0.13). There was a significant weekend effect for acute myocardial infarction (adjusted risk ratio = 1.15, 95% CI: 1.03-1.26, P= 0.007). Two-day in-hospital mortality showed similar results. This is the first Australian study on the 'weekend effect' (in a cohort other than neonates), and the first study worldwide to assess specifically the weekend effect among COPD patients. Observed patterns were consistent with overseas research. There was a significant weekend effect for myocardial infarction. Further research is needed to determine whether location (e.g. rural), clinical (e.g. disease severity) and service provision factors (e.g. access to invasive procedures) influence the weekend effect for acute medical conditions in Australia.
Publisher: American Association for Cancer Research (AACR)
Date: 28-08-2008
DOI: 10.1158/0008-5472.CAN-07-5084
Abstract: We investigated the frequency and function of mutations and increased copy number of the PIK3CA gene in lung cancers. PIK3CA mutations are one of the most common gene changes present in human cancers. We analyzed the mutational status of exons 9 and 20 and gene copy number of PIK3CA using 86 non–small cell lung cancer (NSCLC) cell lines, 43 small cell lung cancer (SCLC) cell lines, 3 extrapulmonary small cell cancer (ExPuSC) cell lines, and 691 resected NSCLC tumors and studied the relationship between PIK3CA alterations and mutational status of epidermal growth factor receptor (EGFR) signaling pathway genes (EGFR, KRAS, HER2, and BRAF). We also determined PIK3CA expression and activity and correlated the findings with effects on cell growth. We identified mutations in 4.7% of NSCLC cell lines and 1.6% of tumors of all major histologic types. Mutations in cell lines of small cell origin were limited to two ExPuSC cell lines. PIK3CA copy number gains were more frequent in squamous cell carcinoma (33.1%) than in adenocarcinoma (6.2%) or SCLC lines (4.7%). Mutational status of PIK3CA was not mutually exclusive to EGFR or KRAS. PIK3CA alterations were associated with increased phosphatidylinositol 3-kinase activity and phosphorylated Akt expression. RNA interference–mediated knockdown of PIK3CA inhibited colony formation of cell lines with PIK3CA mutations or gains but was not effective in PIK3CA wild-type cells. PIK3CA mutations or gains are present in a subset of lung cancers and are of functional importance. [Cancer Res 2008 (17):6913–21]
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2013
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.JTHO.2018.06.015
Abstract: To examine the personal experiences of people with lung cancer and their caregivers and how stigma is manifested throughout a patient's social network. A qualitative thematic analysis of interviews with 28 patients with lung cancer and their caregivers was conducted. Telephone interviews were conducted and transcribed verbatim. Data analysis was guided by contemporary stigma theory. Patients and caregivers reported feeling high levels of felt stigma and concomitant psychological distress in response to the diagnosis of lung cancer. Three overarching themes emerged: the nexus of lung cancer and smoking, moralization, and attacking the link between lung cancer and smoking. Stigma was inevitably linked to smoking, and this formed the hub around which the other themes were organized. Caregivers reported feeling invisible and noted a lack of support systems for families and caregivers. In addition, there was evidence that caregivers experienced stigma by association as members of the patients' close networks. Both groups responded ambivalently to stigmatizing antismoking advertisements. The qualitative analysis demonstrated the complex interplay of the social and personal domains in the experience and outcomes of stigma in lung cancer. There is a significant potential for caregivers of patients with lung cancer to experience exacerbations of psychosocial distress as a consequence of widely shared negative views about lung cancer and its prognosis. It remains for researchers and practitioners to incorporate such complexity in addressing stigma and psychosocial distress in both patients and caregivers.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 12-1996
DOI: 10.1038/BJC.1996.662
Abstract: Some studies have suggested that the S allele of the MYCL oncogene, which results from an intragenic EcoRI restriction fragment length polymorphism (RFLP), may be associated with cancer susceptibility. In addition, this allele has also been linked to metastases and adverse survival in certain cancers, although studies of lung cancer patients from different populations have yielded controversial results. We studied 108 cases of surgical resected non-small-cell lung cancer (NSCLC) and found no evidence that MYCL genotypes were associated with tumour progression or a worse prognosis. However, the presence of loss of heterozygosity (LOH) at this chromosome 1p32 locus correlated significantly with regional lymph node involvement, as well as advanced TNM stage. These data indicate the existence of a chromosome 1p candidate tumour-suppressor gene(s), possibly in linkage disequilibrium with the EcoRI RFLP in specific populations, which appears to play a role in determining tumour progression in NSCLC. Refined mapping of the critical region of loss should help attempts to identify and clone the candidate gene.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.LUNGCAN.2018.07.032
Abstract: Multidisciplinary team (MDT) presentation in lung cancer has the potential to improve longterm outcomes, although this varies between studies. This study aims to evaluate outcomes including survival, according to MDT presentation and to explore the utility of data obtained from local clinical sources. Prospective cases of lung cancer recorded in our institution's cancer registry were analyzed according to MDT presentation for patient and tumour characteristics, adjusted survival and referral to palliative care. 1197 cases were included, 295 (24.6%) with MDT presentation and 902 (75.4%) without. 60% of patients were male with median (IQR) age at diagnosis of 70 years (62-78). Histopathology distribution (non-small cell lung cancer and small-cell lung cancer) was similar between the two groups. Compared with the non-MDT group, the MDT group had (1) ECOG score recorded more often (71.9% vs. 47.6%), (2) higher proportion of ECOG 0 cases (31.2% vs. 11.9%) and ECOG 1 cases (28.8% vs. 20.3%), (3) higher proportion of early stage disease (stage I - 23.1% vs. 9.7% stage II - 10.2% vs. 4.8%, stage IIIA - 14.6% vs 6.3%) and (4) lower proportion of metastatic disease (stage IV - 39.3% vs. 56.1%). Referral to palliative care was incompletely recorded in both groups (MDT: n = 116/295, 39.3% non-MDT: n = 430, 47.7%) but did not differ significantly for stage IV cases. Survival analyzed by stage was greater in the MDT group at 1, 2 and 5 years for all stages except stage IIIB at 1 year post-diagnosis. Adjusted survival analysis for the entire cohort showed improved survival at 5 years for the MDT group (HR 0.7 (0.58-0.85), p < 0.001). MDT presentation is associated with improved adjusted survival for lung cancer in this single institutional cohort in an analysis of local clinical cancer registry data.
Publisher: Oxford University Press (OUP)
Date: 16-08-2000
Abstract: Retinoic acid plays an important role in lung development and differentiation, acting primarily via nuclear receptors encoded by the retinoic acid receptor-beta (RARbeta) gene. Because receptor isoforms RARbeta2 and RARbeta4 are repressed in human lung cancers, we investigated whether methylation of their promoter, P2, might lead to silencing of the RARbeta gene in human lung tumors and cell lines. Methylation of the P2 promoter from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) cell lines and tumor s les was analyzed by the methylation-specific polymerase chain reaction (PCR). Expression of RARbeta2 and RARbeta4 was analyzed by reverse transcription-PCR. Loss of heterozygosity (LOH) was analyzed by PCR lification followed by electrophoretic separation of PCR products. Statistical differences were analyzed by Fisher's exact test with continuity correction. The P2 promoter was methylated in 72% (63 of 87) of SCLC and in 41% (52 of 127) of NSCLC tumors and cell lines, and the difference was statistically significant (two-sided P:<.001). By contrast, in 57 of 58 control s les, we observed only the unmethylated form of the gene. Four tumor cell lines with unmethylated promoter regions expressed both RARbeta2 and RARbeta4. Four tumor lines with methylated promoter regions lacked expression of these isoforms, but demethylation by exposure to 5-aza-2'-deoxycytidine restored their expression. LOH at chromosome 3p24 was observed in 100% (13 of 13) of SCLC lines and 67% (12 of 18) of NSCLC cell lines, and the difference was statistically significant (two-sided P: =.028). Methylation of the RARbeta P2 promoter is one mechanism that silences RARbeta2 and RARbeta4 expression in many lung cancers, particularly SCLC. Chemical demethylation is a potential approach to lung cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 22-09-1998
Abstract: We studied PTEN/MMAC1, a newly discovered candidate tumor suppressor gene at 10q23.3, for mutations in lung cancer. One hundred and thirty-six lung cancer cell line DNAs (66 small cell lung cancers, SCLC, 61 non-small cell lung cancers, NSCLC, four mesotheliomas, five extrapulmonary small cell cancers) were analysed for PTEN/MMAC1 homozygous deletions and five (8%) SCLC lines showed homozygous deletions interrupting the PTEN/MMAC1 gene. Using single stranded conformation polymorphism (SSCP) analysis, we screened the PTEN/MMAC1 open reading frame of 53 lung cancer cell line cDNAs for point mutations and found that 3/35 SCLCs and 3/18 NSCLCs contained homozygous amino acid sequence altering mutations. Northern blot analysis revealed that expression of the PTEN/MMAC1 gene was considerably lower in all the tumor cell lines with point mutations while no expression was detected for cell lines with PTEN/MMAC1 homozygous deletions. Mutation analysis of 22 uncultured, microdissected, primary SCLC tumors and metastases showed two silent mutations, and two apparent homozygous deletions. We also discovered a processed pseudogene (PTEN2) which has 98.5% nt identity to PTEN/MMAC1, that needs to be accounted for in cDNA mutation analysis. Our findings suggest that genetic abnormalities of the PTEN/MMAC1 gene are only involved in a relatively small subset of lung cancers.
Publisher: Wiley
Date: 16-01-2015
DOI: 10.1111/RESP.12457
Publisher: Wiley
Date: 27-04-2023
DOI: 10.1111/RESP.14512
Abstract: See related article
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0735-1097(02)02137-X
Abstract: The goal of this study was to determine whether the cardiostimulant effects of the endogenous beta(1)-adrenergic receptor (AR) agonist, (-)-norepinephrine are modified by polymorphic (Serine49Glycine [Ser49Gly], Glycine389Arginine [Gly389Arg]) variants of beta(1)-ARs in the nonfailing adult human heart. Human heart beta(1)-ARs perform a crucial role in mediating the cardiostimulant effects of (-)-norepinephrine. An understanding of the significance of Ser49Gly and Gly389Arg polymorphisms in the human heart is beginning to emerge, but not as yet in adult patients who have coronary artery disease (CAD). The potency and maximal effects of (-)-norepinephrine at beta(1)-ARs (in the presence of beta(2)-AR blockade with 50 nM ICI 118,551 [erythro-DL-1(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol]) for changes in contractile force and shortening of contractile cycle duration were determined in human right atrium in vitro from 87 patients undergoing coronary artery bypass grafting who were taking beta-blockers before surgery. A smaller s le of patients (n = 20) not taking beta-blockers was also investigated. Genotyping for two beta(1)-AR polymorphisms (Ser49Gly and Gly389Arg) was determined from a s le of blood taken at the time of surgery. (-)-Norepinephrine caused concentration-dependent increases in contractile force and reductions in time to reach peak force and time to reach 50% relaxation. There were no differences in the potency or maximal effects of (-)-norepinephrine in the right atrium from patients with different Ser49Gly and Gly389Arg polymorphisms. The cardiostimulant effects of (-)-norepinephrine at beta(1)-ARs were conserved across Ser49Gly and Gly389Arg polymorphisms in the right atrium of nonfailing hearts from patients with CAD managed with or without beta-blockers.
Publisher: American Thoracic Society
Date: 15-03-2023
Publisher: AME Publishing Company
Date: 02-2018
Publisher: Wiley
Date: 11-04-2018
DOI: 10.1111/RESP.13307
Abstract: While multidisciplinary team (MDT) care in lung cancer is widely practiced, there are few guidelines for MDT on best data collection strategies. MDT meetings need ready access to information for the provision of optimal treatment recommendations (the primary purpose of the meeting), audit of team performance and benchmarking. This study aimed to develop a practical data set designed for these goals through a recognized consensus process with health professionals who participate in formal MDT settings. A modified Delphi process with three iterations (two surveys and one consensus conference) was carried out involving over 100 Australian lung cancer MDT health professionals. In total, 122 lung cancer MDT health professionals responded to the Round 1 survey from over 350 invitees. Of the 122, 98 were available for invitation to Round 2. Of 98, 52 (53%) invitees responded to the Round 2 survey. After two rounds, 51 data elements across 8 domains (patient demographics, risk factors, biopsy data, staging, timeliness, treatment, follow-up and patient selection) achieved consensus, defined as 80% agreement. For Round 3, 33 MDT lead clinicians were invited to participate in a consensus conference. Of 33, 14 (42%) invitees distilled the 47 data elements into 23 elements across 8 domains to address the study objectives. A practical data set for lung cancer MDT to use for optimal treatment recommendations and to evaluate team performance was developed through recognized consensus methodology. Access to streamlined, relevant and feasible data collection strategies may improve MDT decision-making, audit of team performance and facilitate benchmarking.
Publisher: Elsevier
Date: 2006
Publisher: Informa UK Limited
Date: 02-05-2009
DOI: 10.1517/14728220902926119
Abstract: A number of processes lead to epigenetic and epigenomic modifications. To address the importance of epigenomics in respiratory disease. Studies of epigenomics were analysed in relation to chronic respiratory diseases. In lung cancer and mesothelioma, a number of genes involved in carcinogenesis have been demonstrated to be hypermethylated, implicating epigenomic changes in the aetiology of these cancers. Hypermethylated genes have also been associated with lung cancer recurrence, indicating epigenomic regulation of metastasis. In airway diseases, modulation of histone function may activate inflammatory mechanisms in chronic obstructive pulmonary disease patients and lead to relative steroid resistance. There is emerging evidence for the role of epigenetic changes in chronic lung diseases such as asthma, including responses to environmental exposures in utero and to the effects of air pollution. Insight into epigenomics will lead to the development of novel biomarkers and treatment targets in respiratory diseases.
Publisher: Wiley
Date: 24-01-2012
DOI: 10.1111/J.1440-1843.2011.02109.X
Abstract: Particulate matter (PM) emissions involve a complex mixture of solid and liquid particles suspended in a gas, where it is noted that PM emissions from diesel engines are a major contributor to the ambient air pollution problem. While epidemiological studies have shown a link between increased ambient PM emissions and respiratory morbidity and mortality, studies of this design are not able to identify the PM constituents responsible for driving adverse respiratory health effects. This review explores in detail the physico-chemical properties of diesel PM (DPM) and identifies the constituents of this pollution source that are responsible for the development of respiratory disease. In particular, this review shows that the DPM surface area and adsorbed organic compounds play a significant role in manifesting chemical and cellular processes that if sustained can lead to the development of adverse respiratory health effects. The mechanisms of injury involved included inflammation, innate and acquired immunity, and oxidative stress. Understanding the mechanisms of lung injury from DPM will enhance efforts to protect at-risk in iduals from the harmful respiratory effects of air pollutants.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.ENVRES.2018.12.035
Abstract: Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death world-wide by 2020. Prolonged exposure to particulate matter is associated with COPD progression and mortality. Diesel emissions are a major contributor to particulate matter pollution. In this study we test a therapeutic antioxidant, N-acetylcysteine (NAC), for its ability to protect bronchial epithelial cells (pHBECs) from patients with COPD from adverse effects of diesel emission exposure. pHBECs from patients with or without COPD were cultured at air-liquid interface (ALI). Cells were exposed to diesel emissions for 30 min with or without 3-h post-exposure treatment with 5 mM N-acetylcysteine (NAC). Filtered laboratory air was tested as a negative control. Cell responses (cell viability, inflammation and oxidative stress) and gene expression profiles for intracellular and immune signaling were assessed. Diesel emissions exposure increased IL-8 secretion and production, antioxidant production, and cytochrome P450 1a1 (CYP1a1) mRNA expression and suppressed superoxide dismutase-1 (SOD1) mRNA expression in bronchial epithelial cells from COPD patients. Treatment with N-acetyl cysteine attenuated the suppression of SOD1. Nanostring gene expression profiling of the filtered air controls showed COPD epithelial cells have increased expression of MHC class II and an interferon signaling profile. This study indicates that bronchial epithelial cells from COPD patients may be vulnerable to diesel emission exposure due to reduced antioxidant capacity, and elevated CYP1a1 mRNA expression. NAC did not appear to offer protection. Future research will be needed to explore other means of recovering oxidant capacity in COPD airways.
Publisher: Wiley
Date: 30-05-2012
DOI: 10.1002/DC.22877
Abstract: Sclerosing hemangioma (pneumocytoma) is a rare benign lung tumor with uncertain histogenesis but characteristic histology. Reports of the cytopathology of this tumor are even rarer with only a handful of cases in the literature--many of these incorrectly diagnosed by cytology initially. Herein, we describe a case of sclerosing hemangioma diagnosed prima facie by fine-needle aspiration cytology. A cell block preparation with accompanying immunohistochemistry was instrumental in making the diagnosis. A review of the literature is also presented.
Publisher: John Wiley & Sons, Ltd
Date: 18-04-2007
Publisher: BMJ
Date: 29-05-2008
Abstract: There is large variation between in iduals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes ( NQO1 , GSTM1, GSTP1 ) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms ( TNF ) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes ( GSTM1 , GSTP1 ) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene ( GSTM1 ) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for in iduals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.PATHOL.2017.07.001
Abstract: Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 s les resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer s les had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour s les, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank s les for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources.
Publisher: Wiley
Date: 02-04-2015
DOI: 10.1111/RESP.12520
Abstract: There is an increasing trend for the use of multi-disciplinary teams (MDT) in the management of complex medical conditions. The latter may include various cancers, including lung cancer. However, the use of MDT is not restricted to cancer management, but may include complex conditions like diabetes and other non-malignant disorders. There is an increasing trend to use MDT in the investigation and management of patients with suspected or proven lung cancer. This review examines the evidence that supports the efficacy, or otherwise, of lung cancer management in a MDT as opposed to in idual care, who should be a member of a lung cancer MDT, and the specific role of the respiratory physician in a lung cancer MDT. Although it may seem to make common sense to manage lung cancer in a MDT setting, there is actually little in the way of high quality data to support this concept. The logistic and ethical difficulties in researching this issue are highlighted in this review.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Wiley
Date: 15-08-2007
DOI: 10.1111/J.1440-1681.2007.04731.X
Abstract: 1. Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway diseases characterized by airflow obstruction. The beta(2)-adrenoceptor mediates bronchodilatation in response to exogenous and endogenous beta-adrenoceptor agonists. 2. Single nucleotide polymorphisms in the beta(2)-adrenoceptor gene (ADRB2) cause amino acid changes (e.g. Arg16Gly, Gln27Glu) that potentially alter receptor function. Recently, a large cohort study found no association between asthma susceptibility and beta(2)-adrenoceptor polymorphisms. In contrast, asthma phenotypes, such as asthma severity and bronchial hyperresponsiveness, have been associated with beta(2)-adrenoceptor polymorphisms. Of importance to asthma management, coding region polymorphisms may alter the response to short-acting and long-acting beta-adrenoceptor agonists, which are commonly prescribed asthma treatments. 3. Optimizing study design would enhance the robustness of genetic association studies of ADRB2 polymorphisms in airway diseases. Characteristics of high-quality studies include suitable study design and subject selection, optimal study of polymorphisms and haplotypes, disease outcomes of relevance, adequate s le size, adjustment for confounding factors, supportive functional data and appropriate analysis, interpretation and replication. Enhancing these study design factors will provide high-quality evidence regarding the biological and clinical importance of beta(2)-adrenoceptor pharmacogenomics in asthma and COPD.
Publisher: Cambridge University Press (CUP)
Date: 26-04-2010
Publisher: AME Publishing Company
Date: 10-2019
Publisher: AME Publishing Company
Date: 10-2019
Publisher: Wiley
Date: 12-11-2019
DOI: 10.1111/AJCO.13278
Abstract: Multidisciplinary team (MDT) meetings can facilitate optimal lung cancer care, yet details of structured data collection and feedback remain sparse. This study aimed to investigate data collection and the impact of feedback to lung cancer MDTs. A mixed-methods study using pre and post-test surveys, semistructured interviews, and observation to evaluate data collection and response to modeled data feedback in three Australian lung cancer MDTs at different locations and development stage (site A: outer metropolitan, established site B, outer metropolitan, new and site C, inner metropolitan, established). MDT attendees (range 13-25) discussed 5-8 cases per meeting. All sites collected data prospectively (80% prepopulated) into local oncology medical information systems. The pretest survey had 17 respondents in total (88% clinicians). At sites A and C, 100% of respondents noted regular data audits, occasional at site B. Regular audit data included number of cases, stage, final diagnosis, and time to diagnosis and treatment. The post-test survey had 25 respondents in total, all clinicians. The majority (88-96%) of respondents found modeled data easy to interpret, relevant to clinical practice and the MDT, and welcomed future regular data presentations (as rated on a 5-point Likert scale mean weighted average 4.5 where > 4 demonstrates agreement). Semistructured interviews identified five major themes for MDTs: current practice, attitudes, enablers, barriers, and benefits for the MDT. MDT teams exhibited positive responses to modeled data feedback. Key characteristics of MDT data were identified and may assist with future team research and development.
Publisher: AME Publishing Company
Date: 06-2018
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/AH13136
Abstract: Objective Respiratory diseases are a leading cause of morbidity and mortality in Indigenous Australians. However, there are limited approaches to specialist respiratory care in rural and remote communities that are culturally appropriate. A specialist Indigenous Respiratory Outreach Care (IROC) program, developed to address this gap, is described. Methods The aim of the present study was to implement, pilot and evaluate multidisciplinary specialist respiratory outreach medical teams in rural and remote Indigenous communities in Queensland, Australia. Sites were identified based on a perception of unmet need, burden of respiratory disease and/or capacity to use the clinical service and capacity building for support offered. Results IROC commenced in March 2011 and, to date, has been implemented in 13 communities servicing a population of approximately 43 000 Indigenous people. Clinical service delivery has been possible through community engagement and capacity building initiatives directed by community protocols. Conclusion IROC is a culturally sensitive and sustainable model for adult and paediatric specialist outreach respiratory services that may be transferrable to Indigenous communities across Queensland and Australia. What is known about this topic? The high rates of respiratory illnesses in Australian Indigenous children have been poorly explored. There is a dearth of research quantifying and qualifying risk from birth and throughout early childhood, and there are virtually no evidence-based evaluations of interventions to prevent and manage disease. Despite data suggesting an excess burden of disease, there has been little attention paid to respiratory health in this population. The limited research that has been done highlights that a ‘one size fits all’ model will not be effective in all communities, and that health service must meet the needs of communities, be culturally appropriate and be accessible to Aboriginal people for it to be effective and sustainable. The ‘common theme’ is that although health services are improving, service delivery needs to adapt to meet the needs of communities this is not happening quickly enough for many Aboriginal people. What does this paper add? This paper highlights the importance of working with communities in the development and delivery of a culturally appropriate and accessible specialist respiratory service. In addition, this paper acknowledges the importance of recruiting Indigenous staff in the implementation, engagement and delivery of the project. What are the implications for clinicians? This paper provides an outline on how best to deliver a culturally appropriate respiratory outreach service and the role of clinicians, communities and Indigenous staff. This model supports the view that Aboriginal people must be a part of service delivery that is aligned to the ‘holistic concept of health’ for Aboriginal people, thus providing a culturally appropriate service that meets their needs and addresses the health continuum from within culture and community.
Publisher: Wiley
Date: 11-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
Publisher: European Respiratory Society (ERS)
Date: 02-2023
Publisher: Oxford University Press (OUP)
Date: 02-05-2001
Abstract: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung s les, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P =.046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.
Publisher: Public Library of Science (PLoS)
Date: 26-12-2006
Publisher: Elsevier BV
Date: 1995
DOI: 10.1080/00313029500169173
Abstract: In Australia, lung cancer is the most common malignancy in males and the largest cause of cancer deaths. Conventional management has not had a dramatic impact on the mortality rates from lung cancer, which has a case-fatality rate of over 90%. Recent developments in molecular and cellular biology have however, contributed to our knowledge of lung tumorigenesis, which will hopefully translate into clinical benefit for our patients. Many molecular abnormalities are common to both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) but there are differences between these histological types and even within the NSCLC subtypes. This review concentrates on NSCLC, which accounts for up to 85% of Australian lung cancers.
Publisher: Oxford University Press (OUP)
Date: 16-10-2018
DOI: 10.1093/JNCI/DJX216
Publisher: MDPI AG
Date: 06-2023
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the progressive degeneration of the dopaminergic system, leading to a variety of motor and nonmotor symptoms. The currently available symptomatic therapy loses efficacy over time, indicating the need for new therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) has emerged as one of the potential candidates for PD therapy. Intermittent theta burst stimulation (iTBS), an excitatory protocol of rTMS, has been shown to be beneficial in several animal models of neurodegeneration, including PD. The aim of this study was to investigate the effects of prolonged iTBS on motor performance and behavior and the possible association with changes in the NMDAR subunit composition in the 6-hydroxydopamine (6-OHDA)-induced experimental model of PD. Two-month-old male Wistar rats were ided into four groups: controls, 6-OHDA rats, 6-OHDA + iTBS protocol (two times/day/three weeks) and the sham group. The therapeutic effect of iTBS was evaluated by examining motor coordination, balance, spontaneous forelimb use, exploratory behavior, anxiety-like, depressive/anhedonic-like behavior and short-term memory, histopathological changes and changes at the molecular level. We demonstrated the positive effects of iTBS at both motor and behavioral levels. In addition, the beneficial effects were reflected in reduced degeneration of dopaminergic neurons and a subsequent increase in the level of DA in the caudoputamen. Finally, iTBS altered protein expression and NMDAR subunit composition, suggesting a sustained effect. Applied early in the disease course, the iTBS protocol may be a promising candidate for early-stage PD therapy, affecting motor and nonmotor deficits.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.IJNURSTU.2021.104007
Abstract: Safe and high-quality end of life care is not always achieved in acute care hospitals. Nurses represent a key source of information about current practice, and active participants in interventions to improve end of life care in these settings. Examining the volume, type and quality of publications in this field can help to determine whether research is following a natural scientific progression to inform best-practice end of life care. To systematically review: (i) whether the volume and type of publications (i.e. measurement, descriptive or interventions studies) examining nurses' perceptions of, and involvement in, end-of-life care delivered in acute hospitals changed over time (i.e. since 2000) (ii) the proportion of intervention studies involving nurses that meet Risk of Bias research design criteria and (iii) the effectiveness of intervention studies that met minimum Risk of Bias criteria. MEDLINE, Embase, CINAHL, and PsychInfo were searched for data-based papers published in English between Jan 2000 and Dec 2020. Studies were included if they focused on nurses' perceptions of, or role in, the provision of end-of-life care in hospitals. Eligible papers were classified as descriptive, measurement or intervention studies. Intervention studies were assessed against the Risk of Bias methodological criteria for research design, and their effectiveness examined. A total of 131 papers met eligibility criteria for inclusion in the review. The number increased by 31% in each time period (p < 0.0001). Most studies were descriptive (n = 70 53%), 11 were measurement studies (8%), and the remainder were intervention studies (n = 50 38%). Thirteen intervention studies (26%) met eligibility criteria. Methodological quality of the eligible intervention studies was variable. Randomisation and blinding of outcome assessors were the domains of greatest concern. Results were variable, with larger, system-wide interventions that incorporated the expertise of the multidisciplinary healthcare team showing the most promise. There is an increasing number of studies examining nurses' perceptions of, and involvement in, end-of-life care delivered in acute hospitals. The difficulties of conducting intervention research in this field mean that many studies are descriptive in nature. Given the importance of intervention research in establishing causal relationships, larger-scale intervention studies are essential to improving the quality of end-of-life care provided to patients dying in hospital.
Publisher: Hindawi Limited
Date: 22-09-2014
DOI: 10.1111/ECC.12242
Abstract: The traditional roles of Australian cancer registries have been incidence, mortality and survival surveillance although increasingly, roles are being broadened to include data support for health-service management and evaluation. In some Australian jurisdictions, cancer stage and other prognostic data are being included in registry databases and this is being facilitated by an increase in structured pathology reporting by pathology and haematology laboratories. Data linkage facilities are being extended across the country at national and jurisdictional level, facilitating data linkage between registry data and data extracts from administrative databases that include treatment, screening and vaccination data, and self-reported data from large population cohorts. Well-established linkage protocols exist to protect privacy. The aim is to gain better data on patterns of care, service outcomes and related performance indicators for health-service management and population health and health-services research, at a time of increasing cost pressures. Barriers include wariness among some data custodians towards releasing data and the need for clearance for data release from large numbers of research ethics committees. Progress is being made though, and proof of concept is being established.
Publisher: AME Publishing Company
Date: 10-2019
Publisher: Elsevier BV
Date: 03-2018
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 11-2019
DOI: 10.1111/IMJ.14439
Abstract: Lung cancer screening can reduce lung cancer mortality. Australian cost estimates are important to inform policy but remain uncertain. To describe the first direct medical costs associated with lung cancer screening in Australia. Single-centre prospective screening cohort. Healthy volunteers (age 60-74 years, current or former smokers quit 5 years. Non-surgical median survival post-diagnosis was 654 days. Gross trial cost was Australian dollar (AU$) 965 665 (AU$397 396 CT scans AU$29 303 false-positive scan work-up AU$96 340 true-positive scan workup AU$336 914 lung cancer treatment AU$104 712 lung cancer follow-up post-treatment). Average total direct medical cost per participant was AU$3 768. Average direct cost of surgery was AU$22 659 average non-surgical cost was AU$47 395 (radiotherapy, chemotherapy, palliative care). Advanced cancer cost more to treat and had worse survival than early cancer. Screening costs are similar to international studies and suggest that lung cancer early detection could limit treatment costs and improve outcomes.
Publisher: Informa UK Limited
Date: 02-2010
DOI: 10.1586/ERS.09.69
Abstract: The Asian Pacific Society of Respirology (APSR) held its 14th Congress and 3rd Joint Congress of the APSR/American College of Chest Physicians (ACCP) in Seoul, Korea, between 14 and 18 November 2009. It was attended by 1906 delegates from around the world and was particularly well represented by people from the Asia-Pacific Rim. The Congress was highlighted by an excellent scientific program, preceded by an educational course on manuscript preparation and several postgraduate courses. Office Bearers representing the American Thoracic Society, European Respiratory Society and ACCP, amongst others, made significant contributions, further enhancing the high-quality faculty.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 02-02-2017
Publisher: Springer Science and Business Media LLC
Date: 03-09-1998
Abstract: TSG101 is a candidate tumor suppressor gene whose deletion in NIH3T3 cells leads to spontaneous lung metastases in nude mice. Aberrant transcripts of TSG101 have been identified in 47% of primary breast carcinomas, without evidence of intragenic deletions at the TSG101 locus on 11p15. To investigate the possible role of TSG101 in lung cancer, which often shows 11p allele loss, we performed transcript analysis and mutational analysis of TSG101 in lung cancer cell lines. Reverse transcriptase RT-PCR and Northern analysis detected a common TSG101 transcript, shortened because of an internal deletion, which was expressed simultaneously with the wild-type transcript in 89% of small cell lung cancer (SCLC) lines. In contrast, the wild-type transcript was expressed alone in normal tissues, primary non-small cell lung cancer (NSCLC) specimens, and the majority of NSCLC cell lines. Sequence of the shortened SCLC transcript was identical to that of the most common aberrant transcript identified in breast cancer, consisting of a deletion of exons 2-4 and part of 1 and 5. Southern analysis of SCLC lines expressing the shortened transcript did not detect any intragenic deletions. Single strand conformational polymorphism (SSCP) analysis and direct sequencing of TSG101 cDNAs also identified no mutations or deletions. These results suggest that TSG101 is not mutated in lung cancer but that aberrant splicing of TSG101 occurs in SCLC.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.JTHO.2019.11.030
Abstract: We performed a validation study at our institution, the International Union Against Cancer (Union for International Cancer Control latest version of TNM Classification of Malignant Tumors Eighth Edition). Data were collected from the Queensland Oncology Online registry of NSCLC or SCLC cases between 2000 and 2015 and validated against the Queensland Integrated Lung Cancer Outcomes Project registry using case identification number, first name, last name, and date of birth. Where data were available, cases were classified according to the Union for International Cancer Control TNM seventh edition stage groupings and then compared with the eighth edition groupings. Kaplan-Meier curves were plotted, and the log-rank test of survival differences was performed with SPSS version 25 (IBM Corp, Armonk, NY). Of the 3636 cases, 3352 and 1031 had complete clinical and pathologic staging, respectively. Median survival time was found to reduce with increasing clinical stage: seventh edition (IA: 88, IB: 44, IIA: 31, IIB: 18, IIIA: 15, IIIB: 8, and IV: 5 mo) versus eighth edition TNM stage (IA1: not reached, IA2: 88, IA3: 53, IB: 56, IIA: 36, IIB: 22, IIIA: 14, IIIB: 9, IIIC: 8, IVA: 6, and IVB: 3 mo). A similar overall pattern was reflected in the pathologic stage: seventh edition (IA: 124, IB: 110, IIA: 48, IIB: 42, IIIA: 26, IIIB: 31, and IV: 27 mo) versus eighth edition (IA1: not reached, IA2: 122, IA3: 125, IB: 144, IIA: 98, IIB: 57, IIIA: 31, IIIB: 24, and IVA: 7 mo). The log-rank test for survival curves was significant at p < 0.001. Our external validation study confirms the prognostic accuracy of the eighth edition TNM lung cancer classification. Our analyses also indicated that IIIB, IIIC, and IVA stage groups had similar survival outcomes and suggest further research for refinement.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2007
Publisher: Elsevier BV
Date: 07-2005
Abstract: Smoking cessation for current smokers is a health-care imperative. It is not clear which approaches to smoking cessation are the most effective in the hospital setting and which factors predict long-term abstinence. We hypothesized that a hospital-based smoking cessation program involving behavioral modification and support would provide an effective intervention for smoking cessation. Prospective cohort study. Smoking cessation clinics in a tertiary referral, cardiothoracic hospital. Two hundred forty-three smokers and 187 never-smoker control subjects. Smokers underwent specific sessions of in idual counseling on behavioral modification, including written information, advice about quit aids, and support during the quit attempt. Abstinence was confirmed by exhaled carbon monoxide measurements. Compared to never-smoker control subjects, smokers were more likely to have grown up with a smoking father or siblings, and to currently live or socialize with other smokers. Two hundred sixteen smokers attended at least two sessions of the smoking cessation program. Of these, 25% were unavailable for follow-up at 12 months and were assumed to be smoking. The point prevalence abstinence rate at 12 months was 32%. Independent factors associated with abstinence at 12 months were self-belief in quitting ability, having a heart condition, growing up without siblings who smoked, and increasing number of pack-years. This prospective study has demonstrated that this hospital-based smoking cessation program was as effective as programs in other settings. Social and psychological factors were associated with a greater chance of abstinence.
Publisher: American Psychological Association (APA)
Date: 28-09-2023
DOI: 10.1037/PAS0001279
Publisher: Informa UK Limited
Date: 12-2013
DOI: 10.1586/17476348.2013.842468
Abstract: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by persistent airflow limitation. It is the third leading cause of death worldwide, and there are currently no curative strategies for this disease. Many factors contribute to COPD susceptibility, progression and exacerbations. These include cigarette smoking, environmental and occupational pollutants, respiratory infections and comorbidities. As the clinical phenotypes of COPD are so variable, it has been difficult to devise an in idualized treatment plan for patients with this complex chronic disease. This review will highlight how potential clinical, inflammatory, genomic and epigenomic biomarkers for COPD could be used to personalize treatment, leading to improved disease management and prevention for our patients.
Publisher: European Respiratory Society (ERS)
Date: 09-2022
Publisher: BMJ
Date: 07-2017
Publisher: Elsevier BV
Date: 02-2007
Publisher: Springer Science and Business Media LLC
Date: 10-10-2017
Publisher: Annual Reviews
Date: 02-2003
DOI: 10.1146/ANNUREV.MED.54.101601.152202
Abstract: Lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, or the workplace. Recent studies suggest that histologically apparent lung cancer is due to the sequential accumulation of specific genetic and morphologic changes to the normal epithelial cells of the lung. Positive signallers, such as those mediated by the oncogene RAS, and negative signallers, such as those mediated by the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell growth and proliferation. Other key molecular derangements can also be considered hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis, tissue invasion, and metastases. Epigenetic inactivation of genes via DNA methylation provides another novel way of evading normal cellular control mechanisms. The new knowledge of the human genome coupled with global methods of detecting genetic abnormalities and profiling gene expression in tumor cells may enable us to understand the signaling pathways of lung cancer cells. These are molecular targets for new cancer therapeutics such as receptor tyrosine kinase inhibitors. This information could advance risk assessment, early detection, prognosis, and therapy for lung cancer.
Publisher: BMJ
Date: 04-1994
DOI: 10.1136/THX.49.4.382
Abstract: A 40 year old man presented with recurrent episodes of dyspnoea whilst swallowing solid food. He had undergone right pneumonectomy and thoracoplasty for recurrent pneumonias and empyema 23 years previously. Solid food boluses appeared to cause bronchial obstruction by compressing the surgically distorted left main bronchus. This is a new variant of the post pneumonectomy syndrome.
Publisher: Wiley
Date: 03-2004
Publisher: AMPCo
Date: 09-2016
DOI: 10.5694/MJA16.00519
Publisher: Wiley
Date: 21-04-2017
DOI: 10.1002/IJC.30673
Abstract: Lung cancer screening with computerised tomography holds promise, but optimising the balance of benefits and harms via selection of a high risk population is critical. PLCO
Publisher: American Association for Cancer Research (AACR)
Date: 03-2005
DOI: 10.1158/0008-5472.CAN-04-4235
Abstract: Mutations in the epidermal growth factor receptor gene (EGFR) in lung cancers predict for sensitivity to EGFR kinase inhibitors. HER2 (also known as NEU, EGFR2, or ERBB2) is a member of the EGFR family of receptor tyrosine kinases and plays important roles in the pathogenesis of certain human cancers, and mutations have recently been reported in lung cancers. We sequenced the tyrosine kinase domain of HER2 in 671 primary non–small cell lung cancers (NSCLC), 80 NSCLC cell lines, and 55 SCLCs and other neuroendocrine lung tumors as well as 85 other epithelial cancers (breast, bladder, prostate, and colorectal cancers) and compared the mutational status with clinicopathologic features and the presence of EGFR or KRAS mutations. HER2 mutations were present in 1.6% (11 of 671) of NSCLC and were absent in other types of cancers. Only one adenocarcinoma cell line (NCI-H1781) had a mutation. All HER2 mutations were in-frame insertions in exon 20 and target the identical corresponding region as did EGFR insertions. HER2 mutations were significantly more frequent in never smokers (3.2%, 8 of 248 P = 0.02) and adenocarcinoma histology (2.8%, 11 of 394 P = 0.003). In 394 adenocarcinoma cases, HER2 mutations preferentially targeted Oriental ethnicity (3.9%) compared with other ethnicities (0.7%), female gender (3.6%) compared with male gender (1.9%) and never smokers (4.1%) compared with smokers (1.4%). Mutations in EGFR, HER2, and KRAS genes were never present together in in idual tumors and cell lines. The remarkable similarities of mutations in EGFR and HER2 genes involving tumor type and subtype, mutation type, gene location, and specific patient subpopulations targeted are unprecedented and suggest similar etiologic factors. EGFR, HER2, and KRAS mutations are mutually exclusive, suggesting different pathways to lung cancer in smokers and never smokers.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2007
DOI: 10.1158/1078-0432.CCR-07-0216
Abstract: Purpose: Mutation of epidermal growth factor receptor (EGFR) gene has been reported to be present in non–small cell lung cancer (NSCLC) and significantly associated with female sex and never-smoking status. In this study, we extensively investigated the impact of sex and smoking on the EGFR mutation. Experimental Design: We examined EGFR exons 18 to 21 status in 1,467 NSCLC patients by direct sequencing to study the impact of sex and smoking status on the EGFR mutational spectrum. Results: Among 1,467 patients, 197 mutations were found at exon 19, 176 at exon 21, 21 at exon 18, and 24 at exon 20. To examine the independent effect of sex and smoking, the mutational status of each exon was compared between smokers and never smokers in each sex and between males and females stratified by smoking status. In females, exon 19 (P = 0.001) and exon 21 (P & 0.001) mutations were significantly less frequent in ever smokers compared with never smokers. In males, exon 19 (P & 0.001), exon 21 (P & 0.001), and exon 18 (P = 0.003) mutations were significantly less frequent in ever smokers compared with never smokers. In analysis stratified by smoking, there was no difference in sex among never smokers. However, exon 19 mutations were significantly less frequent in males compared with females among ever smokers (P = 0.003). In addition, the interactive effect of male sex and ever smoking status significantly decreased the frequency of exon 19 mutations (P = 0.047) when female never smoker was set as a reference. Conclusion: Both sex and smoking status could influence the EGFR mutational spectrum. Our findings suggest that in idual EGFR exons may have differing susceptibilities for mutagenesis.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: BMJ
Date: 12-1996
Abstract: A 21 year old man presented with a right sided pleural effusion. Destruction of the 11th and 12th right ribs and adjacent vertebral bodies was noted on computed tomographic scanning. An open rib biopsy revealed the histopathological changes of Gorham's syndrome. In view of the progressive vertebral destruction and inevitable spinal cord compromise, he was treated with high dose radiotherapy. The process was arrested and he remains well with no signs of recurrence after four years. Pleural effusion and vertebral destruction complicating Gorham's syndrome carry a poor prognosis but, in this case, high dose radiotherapy has been effective in controlling both the effusion and the progressive bony destruction.
Publisher: Elsevier BV
Date: 08-1998
DOI: 10.1016/S0304-419X(98)00010-9
Abstract: We review the molecular pathogenesis of lung cancer including alterations in dominant oncogenes, recessive oncogenes/tumor suppressor genes, alterations in growth regulatory signaling pathways, abnormalities in other pathways, such as apoptosis, autocrine and paracrine growth stimulatory loops, angiogenesis, and host immune responses, other mechanisms of genetic changes, such as microsatellite and methylation alterations, and the potential for inherited predisposition to lung cancer. These changes are related to multistage carcinogenesis involving preneoplastic lesions, and lung development and differentiation. The translational applications of these findings for developing new ways of early detection, prevention, treatment, and prognosis of lung cancer are discussed.
Publisher: Wiley
Date: 16-01-2018
Publisher: Elsevier BV
Date: 10-2018
Publisher: Oxford University Press (OUP)
Date: 18-03-1998
Abstract: Chromosome 3p14.2 contains FRA3B, the most active chromosome breakage site in the human genome. The fragile histidine triad (FHIT) gene, a putative tumor suppressor gene, overlaps FRA3B. Human papillomavirus (HPV), a known cofactor in cervical carcinogenesis, can integrate into FRA3B. We examined abnormalities in FHIT and its RNA transcripts in cervical cancer cell lines and tumors. We also investigated the relationship between loss of heterozygosity (LOH) in FHIT/FRA3B and the presence of oncogenic HPV types. Eleven cell lines, 40 tumors (20 fresh and 20 archival), and 10 normal cervical epithelia were examined. Two intragenic polymorphic markers (D3S1300 and D3S4103) and the polymerase chain reaction (PCR) were used to examine FHIT LOH. Reverse transcription-PCR (RT-PCR) analysis and single-strand conformation polymorphism analysis of RT-PCR products were used to characterize FHIT transcripts. Oncogenic HPV types were identified by PCR, using general and type-specific primers. All normal epithelia, 19 of 20 fresh tumors and nine of 11 cell lines expressed wild-type and, occasionally, exon 8-deleted FHIT transcripts. Additional aberrant FHIT transcripts were seen in nine of 20 fresh tumors and in seven of 11 cell lines. DNA sequencing of the aberrant transcripts revealed a variety of insertions and deletions but no point mutations. Three cell lines also had homozygous FHIT deletions. Oncogenic HPV types (i.e., 16, 18, 31, and 33) were detected in 18 of 20 archival tumors, and, in these tumors, LOH within FHIT was identified in nine of 16 informative cases. HPV 16 was found to be associated with LOH in the FHIT/FRA3B region (P = .041). FHIT/FRA3B is frequently altered in cervical cancer, demonstrating LOH, occasional homozygous deletions, and frequent aberrant transcripts not found in normal epithelia. However, the presence of wild-type transcripts and the lack of protein-altering point mutations raise questions about FHIT's function as a classic tumor suppressor gene in cervical tissue.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2012
Publisher: Wiley
Date: 26-04-2017
Publisher: Wiley
Date: 06-02-2023
DOI: 10.1111/RESP.14465
Publisher: Wiley
Date: 07-02-2023
DOI: 10.1111/RESP.14464
Publisher: Springer Science and Business Media LLC
Date: 11-03-2003
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.RMED.2005.05.002
Abstract: Morbidity and mortality from lung cancer is a major burden to global health. The integration of expert clinical experience, patient preference and high-quality evidence, including Cochrane systematic reviews, can only help improve outcomes from this highly lethal condition.
Publisher: BMJ
Date: 04-2019
DOI: 10.1136/BMJOPEN-2018-025381
Abstract: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death globally. In outpatient care, the self-management of COPD is essential, but patient adherence to this remains suboptimal. The objective of this study is to examine whether an innovative mobile health (mHealth)-enabled care programme (MH-COPD) will improve the patient self-management and relevant health outcomes. A prospective open randomised controlled trial has been designed. In the trial, patients with COPD will be recruited from The Prince Charles Hospital, Brisbane, Australia. They will then be randomised to participate in either the MH-COPD intervention group (n=50 patients), or usual care control group (UC-COPD) (n=50 patients) for 6 months. The MH-COPD programme has been designed to integrate an mHealth system within a clinical COPD care service. In the programme, participants will use a mHealth application at home to review educational videos, monitor COPD symptoms, use an electronic action plan, modify the risk factors of cigarette smoking and regular physical activity, and learn to use inhalers optimally. All participants will be assessed at baseline, 3 months and 6 months. The primary outcomes will be COPD symptoms and quality of life. The secondary outcomes will be patient adherence, physical activity, smoking cessation, use of COPD medicines, frequency of COPD exacerbations and hospital readmissions, and user experience of the mobile app. The clinical trial has been approved by The Prince Charles Hospital Human Research Ethics Committee (HREC/16/QPCH/252). The recruitment and follow-up of the trial will be from January 2019 to December 2020. The study outcomes will be disseminated according to the Consolidated Standards of Reporting Trials statement through a journal publication, approximately 6 months after finishing data collection. ACTRN12618001091291.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Oxford University Press (OUP)
Date: 19-11-2012
Abstract: DNA methylation is part of the epigenetic gene regulation complex, which is relevant for the pathogenesis of cancer. We performed a genome-wide search for methylated CpG islands in tumors and corresponding non-malignant lung tissue s les of 101 stages I-III non-small cell lung cancer (NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis. Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung tissue s les. Ninety-seven percent of them were found to be tumor-specifically methylated. Annotation of these genomic positions resulted in the identification of 477 tumor-specifically methylated genes of which many are involved in regulation of gene transcription and cell adhesion. Tumor-specific methylation was confirmed by a gene-specific approach. In the majority of tumors, methylation of certain genes was associated with loss of their protein expression determined by immunohistochemistry. Treatment of NSCLC cells with epigenetically active drugs resulted in upregulated expression of many tumor-specifically methylated genes analyzed by gene expression microarrays suggesting that about one-third of these genes are transcriptionally regulated by methylation. Moreover, comparison of methylation results with certain clinicopathological characteristics of the patients suggests that methylation of HOXA2 and HOXA10 may be of prognostic relevance in squamous cell carcinoma (SCC) patients. In conclusion, we identified a large number of tumor-specifically methylated genes in NSCLC patients. Expression of many of them is regulated by methylation. Moreover, HOXA2 and HOXA10 methylation may serve as prognostic parameters in SCC patients. Overall, our findings emphasize the impact of methylation on the pathogenesis of NSCLCs.
Publisher: Wiley
Date: 12-07-2021
DOI: 10.1111/AJCO.13637
Abstract: Systemic therapies for lung cancer are rapidly evolving. This study aimed to describe lung cancer treatment patterns in New South Wales, Australia, prior to the introduction of immunotherapy and latest‐generation targeted therapies. Systemic therapy utilization and treatment‐related factors were examined for participants in the New South Wales 45 and Up Study with incident lung cancer ascertained by record linkage to the New South Wales Cancer Registry (2006–2013). Systemic therapy receipt to June 2016 was determined using medical and pharmaceutical claims data from Services Australia, and in‐patient hospital records. Factors related to treatment were identified using competing risks regressions. A total of 1,116 lung cancer cases were identified with a mean age at diagnosis of 72 years and median survival of 10.6 months. Systemic therapy was received by 45% of cases. Among 400 cases with metastatic non–small cell lung cancer, 51% and 28% received first‐ and second‐line systemic therapy, respectively. Among 112 diagnosed with small‐cell lung cancer, 79% and 29% received first‐ and second‐line systemic therapy. The incidence of systemic therapy was lower for participants with indicators of poor performance status, lower educational attainment, and those who lived in areas of socioeconomic disadvantage and was higher for participants with small‐cell lung cancer histology or higher body mass index. This population‐based Australian study identified patterns of systemic therapy use for lung cancer, particularly small‐cell lung cancer. Despite a universal healthcare system, the analysis revealed socioeconomic disparities in health service utilization and relatively low utilization of systemic therapy overall.
Publisher: Wiley
Date: 31-12-2014
DOI: 10.1002/RCR2.39
Publisher: Oxford University Press (OUP)
Date: 03-2005
DOI: 10.1093/JNCI/DJI055
Abstract: Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue s les from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14% all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.
Publisher: Elsevier BV
Date: 05-2004
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.TIV.2019.02.005
Abstract: Diesel emissions have a high level of particulate matter which can cause inflammation and oxidative stress in the airways. A strategy to reduce diesel particulate matter and the associated adverse effects is the use of biodiesels and fuel additives. However, very little is known about the biological effects of these alternative emissions. The aim of this study is to compare the effect of biodiesel and triacetin/biodiesel emissions on primary human bronchial epithelial cells (pHBECs) compared to diesel emissions. pHBECs were exposed to diesel, biodiesel (20%, 50% and 100% biodiesel derived from coconut oil) and triacetin/biodiesel (4% and 10% triacetin) emissions for 30 min at air-liquid interface. Cell viability (cellular metabolism, cell death, CASP3 mRNA expression and BCL2 mRNA expression), inflammation (IL-8 and IL-6 secretion), antioxidant production (HO-1 mRNA expression) and xenobiotic metabolism (CYP1a1 mRNA expression) were measured. Biodiesel emissions (B50) reduced cell viability, and increased oxidative stress. Triacetin/biodiesel emissions (B90) decreased cell viability and increased antioxidant production, inflammation and xenobiotic metabolism. Biodiesel emissions (B100) reduced cell viability, and increased IL-8 secretion and xenobiotic metabolism. Biodiesel substitution in diesel fuel and triacetin substitution in biodiesel can increase the adverse effects of diesel emissions of pHBECs. Further studies of the effect of these diesel fuel alternatives on pHBECs are required.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.LUNGCAN.2010.08.007
Abstract: We sought (i) lung cancer clinicians' judgements about the smallest survival benefits that would make the harms of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) worthwhile, (ii) factors associated with their judgements, and (iii) comparisons with breast cancer and colon cancer clinicians surveyed similarly in 2002-2003. Delegates at the Australian Lung Cancer Conference 2008 were invited to complete a validated, self-administered questionnaire that used the time trade-off method to determine the minimum survival benefits judged sufficient to make adjuvant chemotherapy worthwhile. The baseline survival times were 3 and 5 years, and the baseline 5-year survival rates were 50% and 65%. Chemotherapy was 4 cycles of cisplatin and vinorelbine. Characteristics of the 156 respondents were: median age 41 years (range 23-62), female 55%, married 83%, with dependent children 62%, respiratory physician 28%, nurse 24%, medical oncologist 14%, radiation oncologist 12%, trial nurse/coordinator 12%, thoracic surgeon 4%. Moderate survival benefits were judged sufficient to make chemotherapy worthwhile. The median benefit judged sufficient was an extra 9 months beyond a baseline survival time of 3 or 5 years. The median benefit judged sufficient was an extra 5% for a baseline survival rate of 65%, versus an extra 10% for a baseline survival rate of 50% (p<0.001). Smaller benefits were judged sufficient by clinicians who were married (p=0.02) or had dependants (p=0.04). Lung cancer clinicians judged smaller benefits sufficient than breast cancer (n=89) and colon cancer (n=72) clinicians in similar prior studies (median required benefit of 9 months versus 12 months, p<0.001). Most lung cancer clinicians attending a national lung cancer conference judged moderate improvements in survival sufficient to make adjuvant chemotherapy worthwhile. Smaller benefits were judged sufficient by lung cancer clinicians in 2008 than by breast cancer and colon cancer clinicians 5-6 years earlier. Clinicians should be aware of their own preferences, and explore their patients' preferences, when discussing adjuvant chemotherapy.
Publisher: Wiley
Date: 29-04-2015
DOI: 10.1002/PON.3829
Abstract: Health-related stigma is associated with negative psychological and quality of life outcomes in lung cancer patients. This study describes the impact of stigma on lung cancer patients' psychological distress and quality of life and explores the role of social constraints and illness appraisal as mediators of effect. A self-administered cross-sectional survey examined psychological distress and quality of life in 151 people (59% response rate) diagnosed with lung cancer from Queensland and New South Wales. Health-related stigma, social constraints and illness appraisals were assessed as predictors of adjustment outcomes. Forty-nine percent of patients reported elevated anxiety 41% were depressed and 51% had high global distress. Health-related stigma was significantly related to global psychological distress and quality of life with greater stigma and shame related to poorer outcomes. These effects were mediated by illness appraisals and social constraints. Health-related stigma appears to contribute to poorer adjustment by constraining interpersonal discussions about cancer and heightening feelings of threat. There is a need for the development and evaluation of interventions to ameliorate the negative effects of health-related stigma among lung cancer patients.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Informa UK Limited
Date: 09-1995
Publisher: Elsevier BV
Date: 12-1999
Publisher: Wiley
Date: 04-1998
DOI: 10.1111/J.1445-5994.1998.TB02967.X
Abstract: In certain non-small cell lung cancer (NSCLC) populations, codon 12 mutations of the KRAS oncogene comprising mostly G-T transversions have diagnostic and prognostic value. However, it is not known if these findings are applicable to all populations of lung cancer patients. To examine for KRAS codon 12 mutations in Australian NSCLC patients. Tumour s les and corresponding normal lung tissue from 108 Australian patients with NSCLC undergoing curative resection were studied for mutations of KRAS codon 12 using a sensitive PCR assay. Mutations were confirmed by DNA sequencing and correlated with histological subtype, tumour stage, the presence of nodal metastases and survival. Eleven KRAS codon 12 mutations were detected in 108 NSCLCs, with most (8/11) occurring in the adenocarcinoma subtype (17% prevalence), but were not associated with adverse outcome or clinico-pathological features. G-T transversions were surprisingly infrequent (37% of adenocarcinoma mutations). These data add to the evidence suggesting geographical differences in the spectrum and significance of KRAS codon 12 mutational genotypes in NSCLC. While these may be due to genetic variation and/or differences in carcinogen exposure, there is a need for larger population based studies before this potentially important biomarker can be recommended universally for optimising lung cancer management.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.JTHO.2019.10.019
Abstract: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobe-specific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for R0, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between R0 and R(un) in pN0 cases. R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies.
Publisher: European Respiratory Society (ERS)
Date: 24-02-2011
DOI: 10.1183/09031936.00190110
Abstract: The clinical applicability of screening surgically resected nonsmall cell lung cancer (NSCLC) tumour tissue and serum for activating epidermal growth factor receptor (EGFR) mutation is unknown. Furthermore, the comparative accuracy of inexpensive EGFR mutation tests, mutant-enriched (ME)-PCR and high-resolution melt (HRM) has not been determined. Lung tumour DNA from 522 surgically resected stage I-IV NSCLC and matched serum DNA from a subset of 64 subjects was analysed for EGFR mutations in exons 19 and 21 using ME-PCR and HRM. Additionally, 97 subjects had previous EGFR DNA sequencing data available for comparison. ME-PCR and HRM detected EGFR mutations in 5% (27 out of 522) of tumour s les. Compared to DNA sequencing, ME-PCR had a sensitivity of 100% and specificity of 99%, while HRM had 100% sensitivity and specificity. Six subjects with EGFR mutation tumours had matched serum, where ME-PCR detected mutations in three s les and HRM in two s les. In the cohort of never-smoker subjects, those with EGFR mutated tumours had worse survival compared with wild-type tumours (30 versus 49 months p=0.017). ME-PCR and HRM have similar accuracy in detecting EGFR mutations but the prognostic implications of the mutations in resected NSCLC warrants further study.
Publisher: Wiley
Date: 12-1999
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.RESINV.2019.06.001
Abstract: Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2007
Publisher: Elsevier BV
Date: 04-2018
Publisher: Oxford University Press (OUP)
Date: 02-2016
DOI: 10.1093/NTR/NTW010
Abstract: Maximizing smoking abstinence in lung cancer screening participants is important to reduce in idual risk of disease and improve screening cost-effectiveness however, the optimal strategy remains undefined. We hypothesized that a single session of tailored face-to-face counseling on the day of screening CT scan, coupled with audio and printed cessation information would be feasible to deliver in a CT screening trial. We randomized volunteer smokers in the Queensland Lung Cancer Screening Study to intervention (counseling session, audio quit materials, printed quit materials, Quitline contact details) or control group (printed quit materials, Quitline contact details). Participants self-reported point prevalence quit rates at 1 year. Fifty-five smokers were enrolled 28 randomized to intervention and 27 controls. Median cigarette consumption was 25/day 54/55 smoked at least 15 cigarettes per day. Median smoking duration was 46 years. Median Fagerström dependence score was 6. In total 58% did not report any quit attempt in the prior 12 months. Mean duration of counseling was 26.5 minutes. After 1 year, four participants (14.3%) in the intervention group and five participants (18.5%) in the control group had quit (P = .74). Combined annual point prevalence quit rate was 16.4%. Although feasible to deliver a single session of tailored counseling on the day of screening this intervention had no discernible impact on cessation over and above printed materials and Quitline access. As participants exhibited hardcore smoking characteristics, more intensive strategies, in larger cohorts, should be explored. The optimal smoking cessation strategy within a lung cancer screening program is not known. This study demonstrates that a single session of counseling can be feasibly delivered on the day of screening but may not have been intensive enough for long-term, hard-core smokers.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 03-2011
Publisher: Wiley
Date: 02-2016
DOI: 10.1111/IMJ.12948
Abstract: Lung cancer incidence, mortality and hospitalisation rates are higher for Indigenous Australians compared with non-Indigenous Australians and increase again when living in more remote areas. If Indigenous Australians are made more aware of lung cancer through better access to health services and programmes, lung cancer outcomes might improve. We aimed to survey the level of lung cancer awareness in rural and remote Aboriginal and Torres Strait Islander communities and discover perceived barriers to timely diagnosis and treatment of lung cancer. Interviews were conducted in three discrete outer regional and remote Aboriginal communities and one urban setting in Queensland. Participants included Aboriginal and Torres Strait Islander peoples from three target population groups: patients referred for medical treatment with symptoms suspicious of lung cancer or confirmed lung cancer Indigenous health workers community members aged 18 years and over. Participants gave written, informed consent. Of 51 community members and 14 Indigenous health workers, 32 reflected they knew very little about lung cancer, 60 cited smoking as the cause of lung cancer and 54 recognised warning symptoms as a prompt to seek healthcare. Indigenous health workers were not able to describe a healthcare pathway that would apply to a patient with suspected lung cancer. The two main barriers identified as impacting on quality healthcare were communication and follow-up processes. These could be addressed by service improvement activities.
Publisher: Oxford University Press (OUP)
Date: 17-09-1997
Abstract: Most lung cancers are attributed to smoking. These cancers have been associated with multiple genetic alterations and with the presence of preneoplastic bronchial lesions. In view of such associations, we evaluated the status of specific chromosomal loci in histologically normal and abnormal bronchial biopsy specimens from current and former smokers and specimens from nonsmokers. Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, and 21 nonsmokers. Polymerase chain reaction-based assays involving 15 polymorphic microsatellite DNA markers were used to examine eight chromosomal regions for genetic changes (loss of heterozygosity [LOH] and microsatellite alterations). LOH and microsatellite alterations were observed in biopsy specimens from both current and former smokers, but no statistically significant differences were observed between the two groups. Among in iduals with a history of smoking, 86% demonstrated LOH in one or more biopsy specimens, and 24% showed LOH in all biopsy specimens. About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage. A subset of biopsy specimens from smokers that exhibited either normal or preneoplastic histology showed LOH at multiple chromosomal sites, a phenomenon frequently observed in carcinoma in situ and invasive cancer. LOH on chromosomes 3p and 9p was more frequent than LOH on chromosomes 5q, 17p (17p13 TP53 gene), and 13q (13q14 retinoblastoma gene). Microsatellite alterations were detected in 64% of the smokers. No genetic alterations were detected in nonsmokers. Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2012
Publisher: Wiley
Date: 07-1994
Abstract: Loss of heterozygosity (LOH) affecting loci at 11p13 and 11p15 occurs in childhood and adult carcinomas, including non-small cell lung cancer (NSCLC). In NSCLC, the highest reported frequency of LOH was 72% at the 11p13 catalase (CAT) locus. As this locus is centromeric to the Wilms' tumour (WT1) locus, possible involvement of WT1 in the pathogenesis of NSCLC was considered. We thus examined 101 cases of NSCLC for LOH at the WT1 and five other polymorphic loci along 11p. At 11p13, the frequencies of LOH were 20% (9/46) at the FSHB locus, 9% (5/53) at the WT1 locus, and 15% (6/41) at the CAT locus. The shortest region of overlap (SRO) at 11p13 was mapped centromeric to, but excluding, the WT1 locus. Only adenocarcinomas showed LOH in this region. At 11p15, LOH affected 23% (18/77) of informative cases, with the highest frequency of 36% at the insulin (INS) locus. The SRO at 11p15 was mapped telomeric to the RRM1 locus. A third region, at 11p13-15 between WT1 and RRM1, was also affected by LOH. LOH at 11p correlated significantly with advanced T stage and nodal involvement in NSCLC tumours. In the squamous cell carcinoma subtype, LOH along 11p also correlated with nodal involvement. Furthermore, squamous tumours with LOH involving 11p13 loci had significantly worse survival than those without LOH. These data suggest that tumor suppressor gene(s) on 11p affect the progression of NSCLC, particularly squamous cell carcinomas.
Publisher: Wiley
Date: 04-1992
Publisher: Elsevier BV
Date: 04-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.JTHO.2018.04.006
Abstract: Health economic evaluations of lung cancer screening with low-dose computed tomography (LDCT) that are underpinned by clinical outcomes are relatively few. We assessed the cost-effectiveness of LDCT lung screening in Australia by applying Australian cost and survival data to the outcomes observed in the U.S. National Lung Screening Trial (NLST), in which a 20% lung cancer mortality benefit was demonstrated for three rounds of annual screening among high-risk smokers age 55 to 74 years. Screening-related costs were estimated from Medicare Benefits Schedule reimbursement rates (2015), lung cancer diagnosis and treatment costs from a 2012 Australian hospital-based study, lung cancer survival rates from the New South Wales Cancer Registry (2005-2009), and other-cause mortality from Australian life tables weighted by smoking status. The health utility outcomes, screening participation rates, and lung cancer rates were those observed in the NLST. Incremental cost effectiveness ratios (ICER) were calculated for a 10-year time horizon. The cost-effectiveness of LDCT lung screening was estimated at AU$138,000 (80% confidence interval: AU$84,700-AU$353,000)/life-year gained and AU$233,000 (80% confidence interval: AU$128,000-AU$1,110,000)/quality-adjusted life year (QALY) gained. The ICER was more favorable when LDCT screening impact on all-cause mortality was considered, even when the costs of incidental findings were also estimated in sensitivity analyses: AU$157,000/QALY gained. This can be compared to an indicative willingness-to-pay threshold in Australia of AU$30,000 to AU$50,000/QALY. LDCT lung screening using NLST selection and implementation criteria is unlikely to be cost-effective in Australia. Future economic evaluations should consider alternative screening eligibility criteria, intervals, nodule management, the impact and cost of new therapies, investigations of incidental findings, and incorporation of smoking cessation interventions.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2000
Publisher: AME Publishing Company
Date: 02-2017
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.JTHO.2019.06.011
Abstract: Lung cancer remains the leading cause of cancer-related mortality worldwide. Tobacco consumption remains the most important risk factor. Although the prevalence of smoking has decreased overall, it continues to be a significant burden for global health. It is estimated that there are still nearly 1 billion cigarette smokers worldwide. Prevention strategies have largely focused on tobacco control and prevention. However, we have witnessed a dramatic increase in the use of e-cigarettes and other vaping products. Primary chemoprevention has historically not been a successful strategy for lung cancer however, focused approaches in specific groups of patients at high risk for development of lung cancer are underway. The majority of cases with NSCLC are diagnosed with locally advanced or metastatic disease, where the overall prognosis remains very poor. Early-stage NSCLC on the other hand has a much better prognosis and can usually be treated radically with either surgical resection or radical radiotherapy, with relatively favorable long-term outcomes. In addition to image-based screening, other methods such as breath-based and biofluid-based approaches are now being investigated for early detection of NSCLC. This review will focus on recent advancements in the field of prevention, screening, and early detection of NSCLC.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 31-05-2006
DOI: 10.1111/J.1440-1843.2006.00859.X
Abstract: Epigenetics is the study of heritable changes in gene expression that occur without changes in DNA sequence. It has a role in determining when and where a gene is expressed during development. Perhaps the most well known epigenetic mechanism is DNA methylation whereby cytosines at position 5 in CpG dinucleotides are methylated. Histone modification is another form of epigenetic control, which is quite complex and erse. Histones and DNA make up the nucleosome which is the structural unit of chromatin which are involved in packaging DNA. Apart from the crucial role epigenetics plays in embryonic development, transcription, chromatin structure, X chromosome inactivation and genomic imprinting, its role in an increasing number of human diseases is more and more recognized. These diseases include cancer, and lung cancer in particular has been increasingly studied for the potential biological role of epigenetic changes with the promise of better and novel diagnostic and therapeutic tools.
Publisher: American Thoracic Society
Date: 15-03-2019
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S0272-5231(03)00062-5
Abstract: This review summarizes the rapidly expanding knowledge of the molecular pathogenesis of lung cancer. It is clear that respiratory epithelial cells require many genetic alterations to become invasive and metastatic cancer. Much more is to be learned, but with modern technology. Clinicians can detect "field cancerized" regions and preneoplastic and malignant cells, therefore offering the opportunity to intercede with biomarker-monitored prevention and early detection efforts. Such molecular screening and detection efforts will likely be coupled to advances in low-dose computed tomographic imaging, positron emission tomography scans, and other imaging modalities. Although this molecular marker approach has great potential, there is not yet a molecular marker validated in large prospective trials that has major independent predictive prognostic value. There is an urgent need for large, adequately powered, carefully designed prospective studies to identify clinically useful new biomarkers. Finally, new therapeutic strategies with genetic manipulation, small molecules, antibodies, vaccines, and, particularly, new drugs targeting specific biologic pathways found to be abnormal in lung provide for future optimism. Researchers need to define their in idual value, especially when integrated with standard therapies.
Publisher: Springer New York
Date: 13-11-2016
Publisher: Wiley
Date: 04-1986
DOI: 10.1111/J.1360-0443.1986.TB00370.X
Abstract: The success of gene therapy in the ocular environment is partly due to the presence of hyaluronan in vitreous. Here we explore the mechanism of hyaluronan-mediated enhancement of adenoviral vector transgene expression. Introduction of hyaluronan receptor CD44 into CD44-negative cells followed by transduction in the presence of vitreous with an adenoviral vector containing an IL-12-coding transgene increases IL-12 secretion. We demonstrate that sequential CD44 proteolysis is responsible for hyaluronan-mediated enhancement. Metalloproteinase or γ-secretase inhibitors decrease adenoviral-mediated transgene expression. Deletion of these proteolytic sites in CD44 also inhibits transgene expression. Expression of CD44 with a mutation to prevent phosphorylation of serine 325 inhibits the response to vitreous. Expression of the CD44 intracellular domain enhances transgene expression in the absence of vitreous. CD44-mediated enhancement of gene expression was observed with vectors using different promoters and appears because of an increase in mRNA production, not because of an increase in vector transduction as determined by quantitative RT-PCR and quantitative PCR, respectively. These data fit a model where the interaction of hyaluronan in vitreous and CD44 modulates transgene expression by initiating CD44 proteolysis and release of the cytoplasmic domain, resulting in increased transgene transcription.
Publisher: Informa Healthcare
Date: 02-02-2011
DOI: 10.1517/14728222.2011.555400
Abstract: Lung cancer and COPD commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer. In addition to smoking cessation and preventing smoking initiation, understanding the shared mechanisms of these smoking-related lung diseases is critical, in order to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD. This review discusses the common mechanisms for susceptibility to lung cancer and COPD, which in addition to cigarette smoke, may involve inflammation, epithelial-mesenchymal transition, abnormal repair, oxidative stress, and cell proliferation. Furthermore, we discuss the underlying genomic and epigenomic changes (single nucleotide polymorphisms (SNPs), copy number variation, promoter hypermethylation and microRNAs) that are likely to alter biological pathways, leading to susceptibility to lung cancer and COPD (e.g., altered nicotine receptor biology). Strategies to study genomics, epigenomics and gene-environment interaction will yield greater insight into the shared pathogenesis of lung cancer and COPD, leading to new diagnostic and therapeutic modalities.
Publisher: American Association for Cancer Research (AACR)
Date: 30-09-2014
DOI: 10.1158/2159-8290.CD-13-0747
Abstract: To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor s les. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 lification or activating mutations. Significance: A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 lification or activating mutations. Cancer Discov 4(10) 1168–81. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1103
Publisher: Wiley
Date: 31-10-2013
Publisher: Wiley
Date: 25-04-2020
DOI: 10.1111/RESP.13823
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 24-01-2012
DOI: 10.1111/J.1440-1843.2011.02083.X
Abstract: The Tumour, Node, Metastasis (TNM) system for classifying lung cancer is the cornerstone of modern lung cancer treatment and underpins comparative research yet is continuously evolving through updated revisions. The recently published Union for International Cancer Control 7th Edition TNM Classification for lung cancer addresses many of its predecessor's shortcomings and has been subject to rigorous evidence-based methodology. It is based on a retrospective analysis of over 80 000 lung cancer patients treated between 1990 and 2000 carried out by the International Association for the Study of Lung Cancer. The dataset was truly international and included patients treated by all modalities. Extensive internal and external validation of the findings has ensured that the recommendations are robust and generalizable. For the first time, a single classification system has been shown to be applicable not only to non-small cell lung cancer, but also to be of prognostic significance in small cell lung cancer and bronchopulmonary carcinoid tumours. We review the history of the Union for International Cancer Control TNM staging system, the changes in the most recent 7th edition and the strength of the scientific basis motivating these changes. Limitations of the current staging edition are explored, post-publication independent validation studies are reviewed, and the future of TNM staging for lung cancer is discussed.
Publisher: British Institute of Radiology
Date: 11-2023
DOI: 10.1259/BJR.20220992
Abstract: Compare accuracy of vertebral Hounsfield Unit attenuation (VHU) and FRAX and Garvan Fracture Risk Calculators in identifying low bone mineral density (BMD) and prevalent vertebral compression fractures (VF) in lung cancer screening (LCS) participants. Baseline CT scans from a single site of the International Lung Screen Trial were analysed. BMD was measured using VHU (of the most caudally imaged vertebra) and quantitative CT (QCT) (low BMD defined as HU and mg/cm 3 respectively). Prevalent VF were classified semi-quantitatively. 10 year FRAX and Garvan fracture risks were calculated using dual energy X-ray absorptiometry (DXA) femoral neck T-score where available. Discrimination was assessed by area under receiver-operating characteristic curves (AUC). 535 LCS participants were included 41% had low VHU-BMD, 56% had low QCT-BMD and 10% had ≥1 VF with ≥25% vertebral height loss. VHU demonstrated 94% specificity and 70% sensitivity in identifying low QCT-BMD. VHU was superior to fracture risk tools in discriminating low QCT-BMD (AUC: VHU 0.94 vs FRAX 0.67, Garvan 0.64 [p 0.05]). In 64 participants with recent DXA scans, VHU was superior to FRAX T-score and Garvan T-score in discriminating low QCT-BMD (AUC: VHU 0.99, FRAX T-score 0.71, Garvan T-score 0.71 [p 0.05]). VHU was non-inferior to FRAX T-score and Garvan T-score in discriminating VF (AUC: VHU 0.65, FRAX T-score 0.53, Garvan T-score 0.61). VHU outperforms clinical risk calculators in detecting low BMD and discriminates prevalent VF equally well as risk calculators with T-scores, yet is significantly simpler to perform. VHU measurement could aid osteoporosis assessment in high-risk smokers undergoing LCS.
Publisher: Elsevier BV
Date: 06-2008
Publisher: Elsevier BV
Date: 06-2018
Publisher: Elsevier BV
Date: 10-2023
Publisher: AMPCo
Date: 11-2013
DOI: 10.5694/MJA13.11110
Publisher: John Wiley & Sons, Ltd
Date: 08-10-2008
Publisher: Elsevier
Date: 2006
Publisher: Wiley
Date: 02-08-2015
Publisher: The Sax Institute
Date: 2019
DOI: 10.17061/PHRP2921910
Abstract: While Australia now has well-established national screening programs for breast, bowel and cervical cancers, research continues into the feasibility of developing systematic screening programs for a number of other cancers. In this paper, experts in their fields provide perspectives on the current state of play and future directions for screening and surveillance for melanoma, Lynch syndrome, and liver, lung and prostate cancers in Australia. Although the evidence does not support population screening, there may be opportunities to prevent thousands of deaths through systematic approaches to the early detection of lung cancer and melanoma, testing for Lynch syndrome, and organised surveillance for hepatocellular carcinoma among in iduals at high risk - guided by targeted research. The paper also looks at what impact new prostate specific antigen testing guidelines are having on screening for prostate cancer.
Publisher: European Respiratory Society (ERS)
Date: 02-04-2015
Publisher: SAGE Publications
Date: 04-12-2012
Abstract: Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.
Publisher: Wiley
Date: 18-10-2019
Abstract: Double perovskites have emerged as efficient candidates for catalyzing the electrochemical oxygen evolution reaction (OER). Smart control of the composition of a B-site ordered double perovskite can lead to improved catalytic performance. By adopting a facile co-doping strategy, the OER-active elements are simultaneously introduced into the B-site and B'-site of a B-site-ordered double perovskite (A
Publisher: Impact Journals, LLC
Date: 05-12-2015
Abstract: In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) s les from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients.
Publisher: Wiley
Date: 2004
DOI: 10.1002/CNCR.20164
Abstract: Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations. p53, its upstream regulators (p14(ARF) and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single-stranded conformation polymorphism analysis covering exons 2-11 and by immunohistochemistry (IHC). p14(ARF) was analyzed by methylation-specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied. Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14(ARF) inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene lification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene lification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down-regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several-fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis. Overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14(ARF), or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs.
Publisher: Elsevier BV
Date: 12-1999
Publisher: Spandidos Publications
Date: 23-06-2015
DOI: 10.3892/OL.2015.3414
Publisher: Wiley
Date: 10-2004
Publisher: Informa UK Limited
Date: 02-2009
Abstract: The Asian Pacific Society of Respirology held its 13th Congress in Bangkok, Thailand, between 19 and 22 November 2008. It was attended by over 1500 delegates from around the world, particularly well represented by delegates from the Asia Pacific Rim. The congress was highlighted by an excellent scientific program, preceded by an educational course on pulmonary laboratory practices and several postgraduate courses. Office bearers representing the American Thoracic Society, European Respiratory Society and American College of Chest Physicians, among others, made significant contributions, further enhancing the high-quality faculty.
Publisher: Public Library of Science (PLoS)
Date: 14-03-2013
Publisher: Elsevier
Date: 2006
Publisher: Bentham Science Publishers Ltd.
Date: 11-2010
Publisher: Elsevier BV
Date: 04-2018
Publisher: Wiley
Date: 17-10-2007
Publisher: American Thoracic Society
Date: 04-2020
Publisher: Elsevier BV
Date: 04-2018
Publisher: John Wiley & Sons, Ltd
Date: 17-10-2007
Publisher: MDPI AG
Date: 28-05-2021
DOI: 10.3390/IJMS22115803
Abstract: Lung cancer remains the leading cause of cancer related mortality worldwide. We aimed to test whether a simple blood biomarker (extracellular vesicle miRNAs) can discriminate between cases with and without lung cancer. Methods: plasma extracellular vesicles (EVs) were isolated from four cohorts (n = 20 in each): healthy non-smokers, healthy smokers, lung cancer, and stable COPD participants. EV miRNA expression was evaluated using the miRCURY LNA miRNA Serum/Plasma assay for 179 specific targets. Significantly dysregulated miRNAs were assessed for discriminatory power using ROC curve analysis. Results: 15 miRNAs were differentially expressed between lung cancer and healthy non-smoking participants, with the greatest single miRNA being miR-205-5p (AUC 0.850), improving to AUC 0.993 in combination with miR-199a-5p. Moreover, 26 miRNAs were significantly dysregulated between lung cancer and healthy smoking participants, with the greatest single miRNA being miR-497-5p (AUC 0.873), improving to AUC 0.953 in combination with miR-22-5p 14 miRNAs were significantly dysregulated between lung cancer and stable COPD participants, with the greatest single miRNA being miR-27a-3p (AUC 0.803), with two other miRNAs (miR-106b-3p and miR-361-5p) further improving discriminatory power (AUC 0.870). Conclusion: this case control study suggests miRNAs in EVs from plasma holds key biological information specific for lung cancer and warrants further prospective assessment.
Publisher: AME Publishing Company
Date: 09-2018
Publisher: Wiley
Date: 17-12-2018
DOI: 10.1111/JOCN.14120
Abstract: To understand the experiences of high-risk respiratory patients undergoing bronchoscopy with conscious sedation. Due to possible complications, high-risk respiratory patients are usually given smaller, cautious doses of sedation and analgesia for bronchoscopy. Described as "conscious sedation," this facilitates depression of the patient's consciousness without causing respiratory compromise. Previously, studies have investigated patient experience using quantitative methods. This is the first study that has explored the patient experience during bronchoscopy from a qualitative perspective. Qualitative, phenomenological approach as described by Van Manen. The setting was an endoscopy unit within an Australian tertiary hospital. Unstructured interviews were conducted with 13 patients with chronic obstructive pulmonary disease who underwent day-case bronchoscopy. All participants received conscious sedation. They were interviewed twice, within a week, postprocedure. Interviews were transcribed verbatim and analysed using Van Manen's interpretive approach. Participants had varying experiences. Five themes emerged from the analysis: Frustration and fear Comfort and safety Choking and coughing Being aware and Consequences. Whilst not all participants experienced procedural awareness or remembered it, for those who did it was a significant event. Overall, experiences were found to be negative however, participants accepted and tolerated them, perceiving them as necessary to obtain a diagnostic result. The findings demonstrate that often patients are aware during the procedure and their experience may be uncomfortable and distressing. These findings have implications for patient preparation pre- and post-bronchoscopy in terms of what they might expect, and to discuss what has happened after the procedure. Some practices of the bronchoscopy team during the procedure may need modification. For ex le, in anticipation of the possibility that the patient may be aware, healthcare professionals should provide patient-focused explanations of what is happening during the procedure, as well as providing ongoing reassurance that everything is going as planned.
Publisher: Informa UK Limited
Date: 11-2022
DOI: 10.2147/COPD.S379774
Publisher: Elsevier BV
Date: 09-2018
Publisher: Future Medicine Ltd
Date: 06-2011
DOI: 10.2217/FON.11.45
Abstract: Malignant pleural effusions (MPEs) are a common and important cause of cancer-related mortality and morbidity. Prompt diagnosis using minimally invasive tests is important because the median survival after diagnosis is only 4–9 months. Pleural fluid cytology is pivotal to current MPE diagnostic algorithms but has limited sensitivity (30–60%). Consequently, many patients need to undergo invasive diagnostic tests such as thoracoscopic pleural biopsy. Recent genomic, transcriptomic, methylation and proteomic studies on cells within pleural effusions have identified novel molecular diagnostic biomarkers that demonstrate potential in complementing cytology in the diagnosis of MPEs. Several challenges will need to be addressed prior to the incorporation of these molecular tests into routine clinical diagnosis, including validation of molecular diagnostic markers in well-designed prospective, comparative and cost–effectiveness studies. Ultimately, minimally invasive diagnostic tests that can be performed quickly will enable clinicians to provide the most effective therapies for patients with MPEs in a timely fashion.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1969-6
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution in acral melanoma, for ex le, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 analyses timings and patterns of tumour evolution 7 describes the erse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 and evaluates a range of more-specialized features of cancer genomes 8,10–18 .
Publisher: Wiley
Date: 28-03-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
Publisher: Oxford University Press (OUP)
Date: 25-04-2019
Abstract: Pleural mesothelioma is a cancer of serosal surfaces caused by environmental exposure to asbestos. Clinical outcome remains poor and while trials of new treatments are ongoing it remains an understudied cancer. Mesothelioma cell lines can readily be grown from primary tumour and from tumour cells shed into pleural effusion with the latter representing a particularly valuable source of DNA in clinical settings, procurable without the need for additional invasive procedures. However, it is not well understood how accurately patient-derived cultured tumour cells represent the molecular characteristics of their primary tumour. We used whole-genome sequencing of primary tumour and matched cultured cells to comprehensively characterize mutations and structural alterations. Most cases had complex rearranged genomes with evidence of chromoanagenesis and rearrangements reminiscent of chromoplexy. Many of the identified driver mutations were structural, indicating that mesothelioma is often caused by structural alterations and catastrophic genomic events, rather than point mutations. Because the majority of genomic changes detected in tumours were also displayed by the genomes of cultured tumour cells, we conclude that low-passage cultured tumour cells are generally suitable for molecular characterization of mesothelioma and may be particularly useful where tissue s les with high tumour cell content are not available. However, the subclonal compositions of the cell lines did not fully recapitulate the subclonal ersity of the primary tumours. Furthermore, longitudinal acquisition of major alterations in subclonal cell populations was observed after long-term passaging. These two factors define limitations of tumour-derived cell lines as genomic substrate for clinical purposes.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2019
DOI: 10.1007/S11356-019-05959-5
Abstract: Diesel emissions contain high levels of particulate matter (PM) which can have a severe effect on the airways. Diesel PM can be effectively reduced with the substitution of diesel fuel with a biofuel such as vegetable oil. Unfortunately, very little is known about the cellular effects of these alternative diesel emissions on the airways. The aim of this study was to test whether coconut oil substitution in diesel fuel reduces the adverse effect of diesel emission exposure on human bronchial epithelial cells. Human bronchial epithelial cells were cultured at air-liquid interface for 7 days and exposed to diesel engine emissions from conventional diesel fuel or diesel fuel blended with raw coconut oil at low (10%), moderate (15%) and high (20%) proportions. Cell viability, inflammation, antioxidant production and xenobiotic metabolism were measured. Compared to conventional diesel, low fractional coconut oil substitution (10% and 15%) reduced inflammation and increased antioxidant expression, whereas higher fractional coconut oil (20%) reduced cell viability and increased inflammation. Therefore, cellular responses after exposure to alternative diesel emission are dependent on fuel composition.
Publisher: BMJ
Date: 10-2003
Abstract: It has been hypothesised that clinically evident lung cancers have accumulated many different genetic or epigenetic abnormalities in oncogenes and/or tumour suppressor genes. This notion has important clinical ramifications. Recent developments in our knowledge of the molecular biology of lung cancer are reviewed, with particular reference to genetic abnormalities in tumour suppressor gene inactivation and overactivity of growth promoting oncogenes. These changes lead to the "hallmarks of lung cancer". These hallmarks are the new rational targets for early detection, prevention, and treatment of lung cancer.
Publisher: AMPCo
Date: 2016
DOI: 10.5694/MJA15.01109
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CCELL.2018.07.001
Abstract: Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal s les. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal s les on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor s les, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor s le that are also predicted major histocompatibility complex-I binders ("putative neoantigens").
Publisher: Public Library of Science (PLoS)
Date: 13-04-2012
Publisher: Wiley
Date: 04-11-2003
DOI: 10.1046/J.1440-1843.2003.00506.X
Abstract: Three confirmed cases of acute iron tablet-induced necrosis due to a fulminant chemical burn injury to the tracheobronchial tree as a result of accidental inhalation and/or aspiration of iron tablets are described. Although histological confirmation has been relied upon for diagnosis, the distinctive bronchoscopic features may allow prompt recognition and treatment by bronchoscopists to prevent this potentially fatal condition.
Publisher: Wiley
Date: 07-2019
DOI: 10.1111/IMJ.14148
Abstract: We report the prevalence and progression of incidentally detected interstitial lung abnormalities (ILA) in the Queensland Lung Cancer Screening Study cohort. About 256 volunteers aged 60-74, with ≥30 pack years smoking history and forced expiratory volume in 1 s (FEV1) ≥50% predicted underwent low-dose computed tomography (CT) chest screening. Electronic search of baseline (T0) and 2-year follow-up (T2) CT reports identified candidate cases using Fleischner Society interstitial terminology. Candidate CT were reviewed in a randomised order by two experienced radiologists and a senior respiratory medicine trainee blinded to the existing reports. Scans were evaluated for the presence and extent of ILA using an in-house score, and graded for progression. ILA were detected in 20/256 baseline cases (7.8%) with no incident cases detected at T2 surveillance imaging. Of these 20 cases, 9 (45%) had reticulation, 18 (90%) had ground glass change, 1 had traction bronchiectasis and 1 had randomly distributed nodularity. Seven cases with ground glass changes also had areas of reticulation, and only two had reticulation alone. All ILA were graded as minor except for traction bronchiectasis, which was moderate. Only one case progressed on T2 imaging. ILA were associated with the presence of auscultatory crackles (50% vs 11.6%, P = 0.001) and a lesser degree of emphysema (mean % volumetric emphysema 6.7% vs 9.8%, P = 0.009). No relationship was observed between baseline and serial lung function parameters. ILA are frequent incidental findings in lung cancer screening. In the majority of cases these abnormalities do not appear to change significantly over a 2-year period of surveillance.
Publisher: BMJ
Date: 22-03-2017
DOI: 10.1136/THORAXJNL-2016-209624
Abstract: High false-positive (FP) scan rates associated with low-dose computed tomography (LDCT) lung cancer screening result in unnecessary follow-up tests and exposure to harm. The definition of a 'positive' scan can impact FP rates and screening performance. We explored the effect of Lung Imaging Reporting and Data System (Lung-RADS) criteria, PanCan Nodule Malignancy Probability Model and varying nodule size thresholds (≥4 mm, ≥6 mm, ≥8 mm) on diagnostic accuracy and screening performance compared with original trial definitions (National Lung Screening Trial (NLST) criteria) in a secondary analysis of a lung cancer screening cohort. We found Lung-RADS criteria and the PanCan Nodule Malignancy Probability Model could substantially improve screening performance and reduce FP scan rates compared with NLST definitions of positivity but that this needs to be balanced against possible risk of false-negative results. Australian New Zealand Clinical Trials Registry, ACTRN12610000007033.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2005
Abstract: Recently, the human SRBC (hSRBC) gene, a candidate tumor suppressor gene (TSG), has been mapped to the chromosomal region 11p 15.5--p15.4 where frequent allele loss has been described in lung cancer. Aberrant methylation (referred to as methylation) of the promoter region of TSGs has been identified as an important mechanism for gene silencing. Loss of hSRBC protein expression occurs frequently in lung cancer cell lines and sodium bisulfite sequencing of the promoter region of hSRBC in several lung cancer cell lines suggested that methylation plays an important role in inactivating hSRBC. To determine the methylation status of hSRBC in a large collection of primary lung cancer s les, corresponding nonmalignant lung tissues and lung cancer cell lines (N=52), we designed primers for a methylation-specific PCR assay. Methylation was detected in 41% of primary non-small-cell lung cancers (NSCLC) (N=107) and in 80% of primary small-cell lung cancers (SCLC) (N=5), but was seen only in 4% of corresponding nonmalignant lung tissues (N=103). In all, 79% of lung cancer cell lines were methylated and the frequency of hSRBC methylation was significantly higher in SCLC (100%) than in NSCLC (58%) cell lines. Normal hSRBC protein expression was detected in only 18% of primary NSCLCs (N=93) by immunostaining and a significant association between loss of protein expression and methylation was found. hSRBC re-expression was observed after treatment of lung cancer cells with the demethylating agent 5-aza-2'-deoxycytidine. In addition, 45% of the 76 hSRBC immunostaining-negative NSCLCs did not have hSRBC promoter methylation, indicating that other mechanisms of hSRBC expression silencing also exist. Both hSRBC immunostaining and methylation results did not correlate with clinicopathological characteristics of these patients. Our findings suggest that hSRBC is a candidate TSG involved in lung cancer pathogenesis, where expression is frequently inactivated by methylation and other mechanisms.
Publisher: Elsevier BV
Date: 06-1999
Publisher: Wiley
Date: 12-01-2019
DOI: 10.1111/RESP.13463
Abstract: The development of molecular testing for identifying somatic mutations and immune checkpoint biomarkers has directed treatment towards personalized medicine for patients with non-small cell lung cancer. The choice of molecular testing in a clinical setting is influenced by cost, expertise in the technology, instrumentation setup and s le type availability. The molecular techniques described in this review include immunohistochemistry (IHC), fluorescent in situ hybridization, direct sequencing, real-time polymerase chain reaction (PCR), denaturing high-performance liquid chromatography, matrix-assisted laser desorption/ionization time of flight mass spectrometry and next-generation sequencing (NGS). IHC is routinely used in clinical practice for the classification, differentiation, histology and identification of targetable alterations of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and programmed death ligand-1 (PD-L1). Recently, the PD-L1 pathway was identified as being exploited by tumour cells, allowing immune resistance and tumour evasion. The development of immune checkpoint inhibitors as treatment for tumours expressing checkpoints has highlighted the need for standardized IHC assays to inform treatment decisions for patients. Direct sequencing was historically the gold standard for mutation testing for EGFR, KRAS (Kirsten rat sarcoma viral oncogene homologue) and BRAF (v-Raf murine sarcoma viral oncogene homologue B1) requiring a high ratio of tumour to normal cells, but this has been superseded by more sensitive methods. NGS is a new emerging technique, which allows high-throughput coverage of frequently mutated genes, including less common BRAF and MET mutations and alterations in tumour suppressor genes. When an NGS platform is unavailable, PCR-based technologies offer an efficient and cost-effective single gene test to guide patient treatment. This article will review these techniques and discuss the future of molecular platforms underpinning clinical management decisions.
Publisher: The Royal Australian College of General Practitioners
Date: 08-2020
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.1007/S00210-002-0652-9
Abstract: Two forms of the activated beta1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant beta1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC50[M] 7.3+/-0.1, E(max) 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta1- and beta2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4+/-0.1, E(max) 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation ( t(50%), -logEC50[M] 7.3+/-0.1, E(max) 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7+/-0.1, E(max) 68+/-6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (-logEC50[M] 7.4+/-0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (-logEC50[M] 7.4+/-0.1, E(max) 34+/-3%, n=13 patients) and hastened the time to peak force (-logEC50[M] 7.6+/-0.1) and time to reach 50% relaxation (-logEC50[M] 7.4+/-0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the beta1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the beta1-adrenoceptor nature of these sites.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2019
Publisher: Wiley
Date: 30-05-2016
DOI: 10.1111/RESP.12809
Publisher: Wiley
Date: 09-1997
DOI: 10.1002/(SICI)1098-2264(199709)20:1<16::AID-GCC3>3.0.CO;2-C
Abstract: Chromosomal or allelic losses at 3p14 are common in a variety of human tumors, including those of the lung, breast, kidney, and head and neck. This suggests the existence of a tumor suppressor gene in this band. A promising candidate is the recently cloned FHIT gene, which spans the common fragile site, FRA3B, at 3p14.2. We previously identified a region of fragility at 3p14.2 (FRA3B) of > 85 kb by cloning DNA flanking pSV2neo integrations and constructed a partial genomic contig of the region. Using probes from the contig, we tested for deletions within this region in DNA from 105 human tumor cell lines, predominantly derived from lung cancers. We identified one gastric and four lung cancer cell lines with homozygous interstitial deletions involving the FRA3B region. The deletion in one lung cancer cell line lies entirely within our contig and is < 65 kb. We have identified, cloned, and sequenced this breakpoint junction. We have also shown that our probes lie within intron S of the FHIT gene and, furthermore, that exon 5 is located approximately 1 kb from one of our probes and, thus, lies within the region of fragility. Two lines with entirely intronic deletions yield FHIT transcripts of normal size. In one of these, this was the sole transcript identified. In the other line, an FHIT transcript completely normal in sequence was accompanied by two larger abnormal transcripts. These results leave open the possibility that some homozygous deletions within the FHIT gene are without phenotypic effect and result from genetic instability of this region. However, taken together, our results provide evidence that breakage and rearrangement within the FRA3B fragile site sequences result in alterations of FHIT and are likely to be involved in carcinogenesis.
Publisher: Elsevier BV
Date: 04-2018
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Kwun Fong.