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Biomedical subjects

Andrew G Nicholson

Publications and source records attributed to Andrew G Nicholson.

At least 55 records · Page 3Linked to original sources
PubMed2003

High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury.

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 +/- 2.9 ml/kg, mean +/- SD) for a duration of 156 +/- 17 min until mean blood pressure fell below 45 mmHg (series 1); high Vt for 120 min (series 2); or low Vt (8.8 +/- 0.5 ml/kg) for 120 or 180 min (series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-alpha in lung lavage fluid at the early stage of injury (series 2) but not the later stage (series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-alpha by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-alpha and MIP-2 proteins and TNF-alpha bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-alpha and MIP-2 expression in mice. The apparently transient nature of TNF-alpha upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

Animals↗
PubMed2003

Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends.

Survival is linked to the histopathologic distinction between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the most commonly encountered fibrotic idiopathic interstitial pneumonia. We retrospectively compared the prognostic significance of histopathologic diagnoses, baseline pulmonary function indices, and serial trends in pulmonary function indices (diffusing capacity, FVC, FEV1, the recently defined composite physiologic index) at 6 and 12 months in 104 patients (UIP, n = 63; fibrotic NSIP, n = 41). Survival was lower in UIP than in fibrotic NSIP (p = 0.001) but not in patients with severe functional impairment; mortality during the first 2 years was linked solely to the severity of functional impairment at presentation. The composite physiologic index was the strongest determinant of outcome (p < 0.001). At 6 months, serial diffusing capacity levels (p = 0.003) and histopathologic diagnosis (p = 0.002) were prognostically equivalent. At 12 months, serial pulmonary function trends were the only major prognostic determinant (p < 0.0005 for all variables), with no independent significance associated with the distinction between UIP and fibrotic NSIP. We conclude that at 12 months, serial pulmonary function trends have considerable prognostic value in UIP and NSIP. Their histologic distinction provides no additional prognostic information when pulmonary function trends are clear cut or when functional impairment is severe.

Aged↗
PubMed2003

Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H pylori in gastric MALT lymphoma.

t(11;18)(q21;q21) is a specific chromosomal translocation associated with mucosa-associated lymphoid tissue (MALT) lymphoma. It fuses the amino terminal of the API2 gene to the carboxyl terminal of the MALT1 gene and generates a chimeric fusion product. Although the translocation is frequently detected in gastric and pulmonary MALT lymphoma, its incidence in MALT lymphomas from other sites is largely unknown. It also remains unknown whether the occurrence of the translocation is influenced by the nature of preceding diseases associated with MALT lymphomas. We screened for t(11; 18)(q21;q21) in 417 cases of MALT lymphoma from 8 major sites by reverse transcription-polymerase chain reaction. t(11;18)(q21;q21) was found at highest frequencies in MALT lymphomas from the lung (38%) and stomach (24%), and at moderate frequencies in those from the conjunctiva (19%) and orbit (14%). However, the translocation was found only rarely in MALT lymphomas from the salivary gland (1%) and was absent in those from the thyroid, skin, liver, and other rare sites, and in immunoproliferative small intestinal disease (IPSID). In gastric MALT lymphoma, t(11;18)(q21;q21) was significantly associated with infection by CagA-positive strains of Helicobacter pylori. As CagA-positive strains of H pylori are much more potent in induction of host inflammatory responses, including activation of neutrophils, which release highly genotoxic oxygen reactive species, we therefore examined neutrophil infiltration in recognized precursors of MALT lymphoma including H pylori-associated gastritis, lymphoepithelial sialadenitis, and Hashimoto thyroiditis. Neutrophil infiltration was prominent in H pylori-associated gastritis but not in lymphoepithelial sialadenitis and Hashimoto thyroiditis. Our results demonstrate that t(11;18)(q21; q21) occurs at markedly variable frequencies in MALT lymphoma of different sites and suggest that the occurrence of the translocation is influenced by the nature of premalignant diseases associated with MALT lymphoma. Oxidative damage might play a role in development of t(11;18)(q21; q21).

Adaptor Proteins, Signal Transducing↗
PubMed2003

Drug-induced pneumonitis and heart failure simultaneously associated with venlafaxine.

Two cases of interstitial pneumonia with cardiac failure developing in patients treated with the new antidepressant venlafaxine are presented. A strong relationship between the development of the patients' illness and the initiation of venlafaxine treatment was identified. The cytochrome P (CYP) 450 system is involved in the metabolism of venlafaxine, suggesting that alterations in the drug metabolic clearance might be, at least in part, responsible for the development of drug-induced damage in these cases. This might occur either as a consequence of a genetic factor or concomitant drug therapy with an inhibitor of the related CYP system. After identifying the causative agent in the first case, withdrawal of the antidepressant together with corticosteroid treatment led to a favorable outcome. In the other case, the multiorgan failure became fatal. These cases highlight a hitherto undescribed association of an adverse lung reaction and heart failure due to venlafaxine.

Adult↗
PubMed2003

Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed by computed tomography.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Aged↗
PubMed2003

Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) and large cell carcinoma with neuroendocrine morphology of the lung are both currently classified as subtypes of large cell carcinomas according to the World Health Organization IASLC classification system for lung and pleural tumors. Prognosis is reported as similar to that of small cell carcinomas. There is no consensus on management of this subset and adjuvant chemotherapy is recommended by some for early stage LCNEC to impact long-term prognosis. We retrospectively reviewed a cohort of patients at our institution who had this type of tumor to determine factors that might influence survival. METHODS: Twenty-one cases of LCNEC and large cell carcinoma with neuroendocrine morphology were identified in the files of the Royal Brompton Hospital between 1986 and 1999. All patient data were reviewed, and complete follow-up was achieved with 20 of these patients. RESULTS: Of the 21 patients identified, 20 underwent resection with systematic nodal dissection in 18. There was no in-hospital mortality. Of those patients fully staged by systematic nodal dissection, 9 were stage I, 5 were stage II and 4 were stage III. Median follow-up was 25 months (range, 2 to 120 months). At the time of review, 11 patients were alive and free of disease. One patient was alive and free of disease when lost to follow-up. Nine patients had died, 7 related and 2 unrelated to disease. The 5-year actuarial survival for the entire group was 47%. The actuarial survival of accurately staged, stage I patients at 5 years was 88%. The actuarial survival of patients in stage II and III was 28% at 5 years. CONCLUSIONS: LCNEC and large cell carcinoma with neuroendocrine morphology are aggressive tumors, but patients with completely resected disease after systematic nodal dissection have a better prognosis than previously described. Patients with more advanced disease have a poor prognosis.

Aged↗
PubMed2003

Liposarcoma of the thyroid gland mimicking retrosternal goiter.

Primary liposarcoma of the thyroid gland is extremely rare with only two previous reports in the literature. We report two further cases, both patients presenting with rapid airways compression. Patient 1 had clinical, radiographic, and biopsy appearances suggesting benign goiter. Patient 2 had a long-term history of benign goiter, a previous partial thyroidectomy, and more recent biopsies showing liposarcoma. The management of such rare conditions is always challenging.

Aged↗
PubMed2003

Smoking-related diffuse parenchymal lung disease: HRCT-pathologic correlation.

Response by the lung to inhaled cigarette smoke varies widely between individuals and ranges from subclinical respiratory bronchiolitis to end-stage Langerhans' cell histiocytosis. The variety of interstitial lung diseases associated with cigarette smoking is wider than generally appreciated, and these often coexist. An understanding of the pathological basis of smoking-related lung disease helps to explain the sometimes complex patterns encountered on high-resolution computed tomography (HRCT). The recent refinement of the classification of the idiopathic interstitial pneumonias and the longitudinal study of cigarette smokers with HRCT has furthered understanding of what should be regarded as an overlapping group of entities. In this article the individual interstitial diseases ascribable to cigarette smoking are discussed in terms of their pathology and corresponding HRCT signs. Emphasis is placed on the frequent coexistence of various forms of smoking-related interstitial lung disease.

Journal Article↗
PubMed2003

Respiratory bronchiolitis-associated interstitial lung disease.

Respiratory bronchiolitis-associated interstitial lung disease (RBILD) can be viewed as an exaggerated respiratory bronchiolitic response to cigarette smoke. The histologic, high-resolution computed tomographic (HRCT) and bronchoalveolar lavage (BAL) features of RBILD overlap substantially with those of respiratory bronchiolitis, with the diagnosis of RBILD being based upon the severity of disease, as judged by symptoms, clinical signs, the severity of lung function impairment, and the extent of abnormalities on HRCT. Typical histologic appearances consist of an accumulation of pigmented macrophages within respiratory bronchioles, associated with peribronchial chronic inflammatory cell infiltration and, variably, peribronchial fibrotic alveolar septal thickening. Characteristic HRCT findings include poorly defined centrilobular micronodules, patchy limited ground-glass attenuation, bronchial wall thickening, and areas of regional hypoattenuation. The ventilatory defect is often mixed but is usually predominantly restrictive. The diagnosis of RBILD is often made on clinical and HRCT criteria, with BAL findings providing useful diagnostic support, but a thoracoscopic biopsy continues to be required when other features are atypical. RBILD may regress with discontinuation of smoking but often persists with no functional improvement despite smoking cessation and treatment. Nonetheless, the course tends to be benign, without inexorable deterioration. This article outlines the rationale for viewing RBILD and desquamative interstitial pneumonia as separate entities, rather than two ends of the same disease spectrum (based upon overlapping histologic and HRCT features).

Journal Article↗
PubMed2003

An assessment of the expanded classification of congenital cystic adenomatoid malformations and their relationship to malignant transformation.

The purpose of this study was to review cases of congenital cystic adenomatoid malformations (CCAMs) arising in children and adults, in order to assess the recently expanded classification system for these lesions and their association with malignant transformation. Of 28 CCAMs, there were 16 type 1, 4 type 2, and 8 type 4 lesions, 12 of which presented in adults. Five of 16 type 1 CCAMs were accompanied by microscopic foci of bronchioloalveolar carcinoma; two others showed focal mucous cell hyperplasia. In two further cases, foci of nonmucinous atypical adenomatous hyperplasia were identified in the adjacent lung parenchyma. The bronchioloalveolar carcinomas showed less cytologic atypia, proliferative activity (Ki-67), and p53 expression than a comparative group of bronchioloalveolar carcinomas arising de novo, but this was not statistically significant (p = 0.15). Neither bronchioloalveolar carcinomas nor hyperplasia was identified in type 2 or type 4 CCAMs. Four of the eight type 4 CCAMs showed focal stromal hypercellularity, and one case subsequently developed a pleuropulmonary blastoma. We conclude that classification according to the current system is of clinical value. Bronchioloalveolar carcinomas arise in association with type 1 CCAMs, but recurrence following resection is exceptional. Type 4 CCAMs show histologic overlap with grade 1 pleuropulmonary blastomas, and distinction between these entities may not be possible on histology alone. However, stromal cellularity in a type 4 CCAM should raise the possibility of blastomatous transformation.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2003

Terminal diffuse alveolar damage in relation to interstitial pneumonias. An autopsy study.

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.

Aged↗
PubMed2003

A clinicopathologic study of 12 neuroendocrine tumors arising in the thymus.

STUDY OBJECTIVES: To determine whether the new classification system for thymic carcinoid tumors/neuroendocrine carcinomas provides prognostic data, and to study the presentation, diagnosis, treatment, and prognostic factors of these rare tumors. DESIGN: Retrospective analysis. SETTING: Royal Brompton Hospital, London, UK. RESULTS: Eight men and four women with a median age of 58 years. Complete excision was possible in nine patients. Postoperative staging revealed two stage I tumors, two stage II tumors, three stage III tumors, one stage IVA tumor, and four stage IVB tumors. All tumors demonstrated the histopathologic features of neuroendocrine tumors, which were confirmed by positive immunohistochemical staining for chromogranin A in 11 of 12 tumors and for CD56 in 12 of 12 tumors, and the presence of dense core granules on ultrastructural analysis in 9 of 9 tumors. All 12 tumors did not stain positively for somatostatin receptors. Three tumors were grade 1, six cases were grade 2, and three cases were grade 3. Follow-up was available in all patients. One patient died 1 month postoperatively. Distant metastasis developed in nine patients (82%). Local recurrence was evident in six patients, of whom five had not received postoperative radiotherapy. Seven patients died of distant metastasis (22 to 83 months after surgery). Two are alive and disease-free (at 67 and 81 months), and two are alive with disease (at 60 and 86 months) CONCLUSIONS: Neither grading as neuroendocrine carcinomas nor any individual histologic parameter showed a significant association with prognosis. Initial aggressive treatment, including complete surgical excision and adjuvant radiotherapy, appears to offer the best hope for prolonged survival. Adjuvant chemotherapy also should be considered, since the incidence of distant relapse is high.

Carcinoid Tumor↗
PubMed2002

Interstitial vascularity in fibrosing alveolitis.

The aim of this study was to evaluate interstitial vascularity in cryptogenic fibrosing alveolitis (CFA) and in fibrosing alveolitis associated with systemic sclerosis (FASSc). Open lung biopsies from eight patients with CFA, nine patients with FASSc, and normal lung from 12 patients undergoing surgery for lung cancer were studied. Markers for endothelial cells (CD34) and cell proliferation (proliferating cell nuclear antigen) were localized by sequential immunohistochemistry and quantified using computer-assisted analysis. Vascular distribution was evaluated at increasing distances (up to 160 microm) from the airspaces. Vessel density was markedly reduced in both FASSc (3.9%) and in CFA (4.5%) compared with control samples (20.4%, p < 0.0001). The percentage of tissue occupied by vessels decreased with increasing distance from alveoli in control samples but not in CFA or FASSc samples. Endothelial cell proliferation indices were increased in FASSc but not in CFA, compared with control samples (p = 0.006). In conclusion, there is net vascular ablation and redistribution of blood vessels in areas of interstitial thickening in both CFA and FASSc, which may contribute to gas exchange impairment.

Adult↗
PubMed2002

The relationship between individual histologic features and disease progression in idiopathic pulmonary fibrosis.

We have retrospectively studied 53 patients with idiopathic pulmonary fibrosis and a histologic diagnosis of usual interstitial pneumonia and evaluated the prognostic significance of four individual histologic features (fibroblastic foci [FF], interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages) using a semiquantitative scale of 0-6. An objective count of FF was also undertaken. Using weighted kappa coefficients, interobserver agreement between pathologists was moderate to good (0.56-0.76). Subjective and objective FF scores were strongly associated (R(S) = 0.88, < 0.00005). Mortality was independently linked to a high FF score, p = 0.006, and a low percent predicted carbon monoxide diffusing capacity (DL(CO)), p = 0.01. For pulmonary function, on univariate analysis, the strongest correlations were observed between increasing interstitial mononuclear cell infiltrate or FF scores and greater declines in forced vital capacity (FVC) or DL(CO) at 6 months. Multivariate models revealed that increasing FF scores were independently associated with greater declines in FVC and DL(CO) at both 6 and 12 months. Increasing interstitial mononuclear cell infiltrate scores were also independently linked to functional decline, but only at 6 months. These data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with idiopathic pulmonary fibrosis.

Biopsy↗
PubMed2002

Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.

Fibrosing alveolitis associated with systemic sclerosis (FASSc) has a better prognosis than idiopathic pulmonary fibrosis. In view of recent reports that idiopathic nonspecific interstitial pneumonia (NSIP) has a better prognosis than idiopathic usual interstitial pneumonia (UIP), we classified histologic appearances of surgical lung biopsies performed in 80 patients with FASSc. NSIP (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47) was much more prevalent than UIP (n = 6), end-stage lung disease (ESL, n = 6), or other patterns (n = 6). There were 25 deaths (NSIP 16/62, 26%; UIP/ESL 6/12, 50%). Five-year survival differed little between NSIP (91%) and UIP/ESL (82%); mortality was associated with lower initial carbon monoxide diffusing capacity (DL(CO)) and FVC levels (p = 0.004 and p = 0.007, respectively). Survival and serial FVC and DL(CO) trends did not differ between cellular and fibrotic NSIP. Increased mortality in NSIP was associated with lower initial DL(CO) levels (p = 0.04), higher BAL eosinophil levels (p = 0.03), and deterioration in DL(CO) levels during the next 3 years (p < 0.005). We conclude that NSIP is the histopathologic pattern in most patients with FASSc. However, outcome is linked more strongly to disease severity at presentation and serial DL(CO) trends than to histopathologic findings.

Adult↗
PubMed2002

Successful treatment of endogenous lipoid pneumonia due to Niemann-Pick Type B disease with whole-lung lavage.

In Type B Niemann-Pick disease, progressive pulmonary infiltration is a major cause of morbidity and mortality, although the disease is usually diagnosed before adulthood in other organ systems. To date, no successful treatment of pulmonary involvement by Niemann-Pick disease has been documented. We describe the case of a patient with Niemann-Pick Type B disease who presented with extensive endogenous lipoid pneumonia and life-threatening hypoxia following bypass grafting for severe coronary artery disease. A surgical lung biopsy at the time of grafting revealed characteristic histology and ultrastructural features of Niemann-Pick disease, with confirmatory findings in biochemical studies. Because of the severity of the patient's symptoms, bilateral whole-lung lavage was undertaken, leading to symptomatic improvement, lessening of parenchymal opacification on high-resolution computed tomographic scanning, and a marked improvement in resting arterial oxygen tension while breathing air to 10.3 kPa from 8.4 kPa. Whole-lung lavage may be a potentially useful modality of treatment for patients with pulmonary involvement by Niemann-Pick Type B disease.

Anti-Inflammatory Agents↗