Showing papers by "Andrew G. Nicholson published in 2004"

Lung cancer: intragenic ERBB2 kinase mutations in tumours.

Abstract: The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.

CT features of lung disease in patients with systemic sclerosis: Comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia

Abstract: PURPOSE: To evaluate computed tomographic (CT) patterns of lung disease in patients with systemic sclerosis (SSc) and compare them with CT appearance in patients with biopsy-proved idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (NSIP) MATERIALS AND METHODS: The CT features of consecutive patients with SSc (n = 225; male patients, 44; female patients, 181; median age, 47 years; age range, 16–78 years), IPF (n = 40; men, 26; women, 14; median age, 545 years; age range, 36–77 years) and NSIP (n = 27; men, 18; women, nine; median age, 53 years; age range, 32–68 years) were quantified separately by two observers The extent of interstitial lung disease, ground-glass opacification, emphysema, and the coarseness of a reticular pattern were quantified Group comparisons were made nonparametrically with the Wilcoxon rank sum test Differences in CT features were identified with multiple logistic regression analysis RESULTS: The coarseness of fibrosis was similar in patient

Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis

Abstract: Aims and methods: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non-specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjogren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. Results and conclusions: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjogren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.

Inter-observer variation between pathologists in diffuse parenchymal lung disease

Abstract: Background: There have been few inter-observer studies of diffuse parenchymal lung disease (DPLD), but the recent ATS/ERS consensus classification provides a basis for such a study. Methods: A method for categorising numerically the percentage likelihood of these differential diagnoses was developed, and the diagnostic confidence of pathologists using this classification and the reproducibility of their diagnoses were assessed. Results: The overall kappa coefficient of agreement for the first choice diagnosis was 0.38 (n = 133 biopsies), increasing to 0.43 for patients (n = 83) with multiple biopsies. Weighted kappa coefficients of agreement, quantifying the level of probability of individual diagnoses, were moderate to good (mean 0.58, range 0.40–0.75). However, in 18% of biopsy specimens the diagnosis was given with low confidence. Over 50% of inter-observer variation related to the diagnosis of non-specific interstitial pneumonia and, in particular, its distinction from usual interstitial pneumonia. Conclusion: These results show that the ATS/ERS classification can be applied reproducibly by pathologists who evaluate DPLD routinely, and support the practice of taking multiple biopsy specimens.

HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation

Abstract: Background: This study was designed to measure inter-observer variation between thoracic radiologists in the diagnosis of diffuse parenchymal lung disease (DPLD) using high resolution computed tomography (HRCT) and to identify areas of difficulty where expertise, in the form of national panels, would be of particular value. Methods: HRCT images of 131 patients with DPLD (from a tertiary referral hospital (n = 66) and regional teaching centres (n = 65)) were reviewed by 11 thoracic radiologists. Inter-observer variation for the first choice diagnosis was quantified using the unadjusted kappa coefficient of agreement. Observers stated differential diagnoses and assigned a percentage likelihood to each. A weighted kappa was calculated for the likelihood of each of the six most frequently diagnosed disease entities. Results: Observer agreement on the first choice diagnosis was moderate for the entire cohort (κ = 0.48) and was higher for cases from regional centres (κ = 0.60) than for cases from the tertiary referral centre (κ = 0.34). 62% of cases from regional teaching centres were diagnosed with high confidence and good observer agreement (κ = 0.77). Non-specific interstitial pneumonia (NSIP) was in the differential diagnosis in most disagreements (55%). Weighted kappa values quantifying the likelihood of specific diseases were moderate to good (mean 0.57, range 0.49–0.70). Conclusion: There is good agreement between thoracic radiologists for the HRCT diagnosis of DPLD encountered in regional teaching centres. However, cases diagnosed with low confidence, particularly where NSIP is considered as a differential diagnosis, may benefit from the expertise of a reference panel.

Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a Selective Inhibitor of Phosphodiesterase 7: In Vitro Studies in Human Monocytes, Lung Macrophages, and CD8+ T-Lymphocytes

Abstract: The biochemical and pharmacological characteristics in human proinflammatory cells of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a novel and selective inhibitor of phosphodiesterase (PDE) 7, are described. BRL 50481 inhibited the activity of hrPDE7A1 expressed in baculovirus-infected Spodoptera frugiperda 9 cells in a competitive manner (Ki value of 180 nM) and was 416 and 1884 times less potent against PDE3 and 38 and 238 times less potent against PDE4 at a substrate concentration of 1 μM and 50 nM cAMP, respectively. Western blotting identified HSPDE7A1 but not HSPDE7A2 in three human cell types that are implicated in the pathogenesis of chronic obstructive lung disease, namely, CD8+ T-lymphocytes, monocytes, and lung macrophages. BRL 50481 had no effect on the proliferation of CD8+ T-lymphocytes and only marginally (∼2-11%) reduced the generation of tumor necrosis factor (TNF)α from blood monocytes and lung macrophages. However, in the presence of BRL 50481 the inhibitory effect of rolipram was enhanced on all three cell types. The expression of HSPDE7A1 was increased in a time-dependent manner in monocytes that were “aged” in culture medium. Under this condition, BRL 50481 now inhibited TNFα generation in a concentration-dependent manner. In aged monocytes, rolipram, Org 9935 (a PDE3 inhibitor), and prostaglandin E2 inhibited TNFα generation in a concentration-dependent manner and interacted additively with BRL 50481. BRL 50481 is the first fully documented PDE7 inhibitor that has acceptable selectivity for in vitro studies. Furthermore, although BRL 50481 had only a modest inhibitory effect per se on the proinflammatory cells studied, it acted at least additively with other cAMP-elevating drugs, especially when HSPDE7A1 was up-regulated.

Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking.

Abstract: Aims : Respiratory bronchiolitis (RB) and desquamative interstitial pneumonia (DIP) are closely associated histological patterns of interstitial pneumonia, although there are no studies on the extent of individual histological parameters. Furthermore, the term smoking related-interstitial lung disease (SR-ILD) has been proposed as a term to encompass patients with both these histological patterns who give a history of smoking, though it is not well defined how this term relates to historical cases of DIP. The aim of this study was to compare histological parameters in cases of DIP and RB and then to review in detail clinical, imaging and histological data for DIP in relation to a history of smoking. Methods and results : Forty-nine cases were reviewed, 24 with RB and 25 with DIP; five cases of DIP were re-classified as RB on review due to bronchocentricity of the infiltrate. There was a significantly greater extent of interstitial fibrosis (P = 0.02), lymphoid follicles (P < 0.001) and eosinophilic infiltration (P < 0.0001) in patients with DIP compared with RB. In addition, the extents of these three parameters were significantly interrelated. Patients with DIP had a lower incidence of smoking (60%) when compared with patients with RB-ILD (93%) (P < 0.005). Further analysis of smokers versus never-smokers with DIP showed no difference in histological parameters, extent of haemosiderin deposition or the number of CD1a+ macrophages between the two groups, nor were there any differences in clinical data to suggest other aetiologies. Follow-up high-resolution computed tomography data from patients with DIP suggested that a pattern of fibrotic non-specific interstitial pneumonia (NSIP) may develop in the long term in both smokers and never-smokers. Conclusion : There are significant differences in the extent of interstitial fibrosis, lymphoid follicles and eosinophilic infiltration between DIP and RB, as well as a much lower incidence of smoking in patients with DIP. Whether the lower reported incidence of smoking in DIP reflects referral bias or conservatism in giving a history of smoking remains uncertain, as neither histological parameters nor clinical data indicate a difference between smokers and never-smokers with DIP. Nevertheless, some cases of DIP are likely to remain idiopathic and unrelated to RB, though still have a good prognosis. Furthermore, they may evolve into a pattern resembling fibrotic NSIP. Therefore, whilst SR-ILD is appropriate in the correct clinical setting, the distinction between the histological patterns of RB and DIP remains appropriate.

Gene expression profiling reveals novel TGFβ targets in adult lung fibroblasts

Abstract: Background Transforming growth factor beta (TGFβ), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFβ on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown.

Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome

Abstract: Objective:We aimed to quantify concentrations of inducible heme oxygenase (HO)-1 in the lungs of patients with acute respiratory distress syndrome (ARDS) and to investigate its role as a source of ferrous iron and as a signaling agent for iron regulation. Control of such processes by heme oxygenase

LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription

Abstract: LIM domains-containing protein 1 (LIMD1) is encoded at chromosome 3p21.3, a region commonly deleted in many solid malignancies. However, the function of LIMD1 is unknown. Here we show that LIMD1 specifically interacts with retinoblastoma protein (pRB), inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. LIMD1 blocks tumor growth in vitro and in vivo and is down-regulated in the majority of human lung cancer samples tested. Our data indicate that LIMD1 is a tumor-suppressor gene, the protein product of which functionally interacts with pRB and the loss of which promotes lung carcinogenesis.

A fatal case of disseminated aspergillosis caused by a non- sporulating strain of Aspergillus fumigatus

Abstract: This report describes the case of a 38 year old pregnant woman with fatal disseminated aspergillosis and multiorgan failure, which was preceded by a long history of allergic bronchopulmonary aspergillosis. Postmortem revealed massive infarction and abscess formation in both lungs. Histology revealed a focal granulomatous response. Fungal infiltration with areas of necrosis were also seen in the liver, spleen, and paratracheal, mediastinal, para-aortic, and hilar lymph nodes. Culture of tissue samples produced a non-sporulating, beige coloured fungus that developed green pigmentation only after three weeks of incubation. Nucleotide sequencing of the D1–D2 region of the large ribosomal subunit revealed 100% homology with Aspergillus fumigatus. Minimum inhibitory concentrations for amphotericin B and itraconazole were both 0.25 mg/litre (susceptible). Further work is urgently required to determine the prevalence of such non-sporulating strains and their relevance to clinical infection.

Pulmonary masses presenting 11 years after abdominal surgery - Diagnosis: Pulmonary hyalinizing granuloma

Abstract: Accessible online at: www.karger.com/res A 21-year-old female smoker of Afro-Caribbean origin presented with vague episodes of non-specific abdominal pain and underwent a laparotomy 3 years later. Pre-operative thoracic imaging was unremarkable. At surgery, a mass arising from the left kidney, involving the spleen, gastric wall and pancreatic tail was completely excised. Histology was compatible with a diagnosis of intraabdominal desmoid, but after re-evaluation was reclassified as a hyalinized variant of retroperitoneal fibrosis. The patient remained asymptomatic on follow-up until 11 years later (aged 32 years), when she developed an intractable cough. Chest X-ray (fig. 1) demonstrated a number of pulmonary masses. Computerized tomography (CT; fig. 2) revealed that the largest of these measured 6 ! 3 cm, and was cavitating (fig. 2). There were no other radiological abnormalities. Full blood count, serum electrolytes, autoantibody screening, angiotensin-converting enzyme level, paired serology for atypical organisms, viral titres, and sputum analysis for bacteria including acid fast bacilli were within normal limits. Serum precipitins were also absent. However, the erythrocyte sedimentation rate was elevated at 61mm in the 1st h. Fibre-optic bronchoscopy with broncho-alveolar lavage showed normal appearances with no evidence of acid fact bacilli, fungi, or malignancy. Thoracotomy and open biopsy demonstrated hyalinized fibrous tissue with a patchy mononuclear inflammatory cell infiltrate, consistent with reactive fibrosis. There was no evidence of malignancy. The patient’s symptoms remained stable over the next 4 years, although serial CT imFig. 1. Chest X-ray demonstrating mass in right mid-zone with further lesions at left apex. Fig. 2. Thoracic CT showing a cavitating mass in the right lung extending towards the right hilum (white arrow).