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Biomedical subjects

Peter Goldstraw

Publications and source records attributed to Peter Goldstraw.

At least 19 recordsLinked to original sources
PubMed2007

Differential regulation of cytokine release and leukocyte migration by lipopolysaccharide-stimulated primary human lung alveolar type II epithelial cells and macrophages.

Bacterial colonization is a secondary feature of many lung disorders associated with elevated cytokine levels and increased leukocyte recruitment. We hypothesized that, alongside macrophages, the epithelium would be an important source of these mediators. We investigated the effect of LPS (0, 10, 100, and 1000 ng/ml LPS, up to 24 h) on primary human lung macrophages and alveolar type II epithelial cells (ATII; isolated from resected lung tissue). Although macrophages produced higher levels of the cytokines TNF-alpha and IL-1beta (p < 0.0001), ATII cells produced higher levels of chemokines MCP-1, IL-8, and growth-related oncogene alpha (p < 0.001), in a time- and concentration-dependent manner. Macrophage (but not ATII cell) responses to LPS required activation of ERK1/2 and p38 MAPK signaling cascades; phosphorylated ERK1/2 was constitutively up-regulated in ATII cells. Blocking Abs to TNF-alpha and IL-1beta during LPS exposure showed that ATII cell (not macrophage) MCP-1 release depended on the autocrine effects of IL-1beta and TNF-alpha (p < 0.003, 24 h). ATII cell release of IL-6 depended on autocrine effects of TNF-alpha (p < 0.006, 24 h). Macrophage IL-6 release was most effectively inhibited when both TNF-alpha and IL-1beta were blocked (p < 0.03, 24 h). Conditioned media from ATII cells stimulated more leukocyte migration in vitro than conditioned media from macrophages (p < 0.0002). These results show differential activation of cytokine and chemokine release by ATII cells and macrophages following LPS exposure. Activated alveolar epithelium is an important source of chemokines that orchestrate leukocyte migration to the peripheral lung; early release of TNF-alpha and IL-1beta by stimulated macrophages may contribute to alveolar epithelial cell activation and chemokine production.

Antibodies, Blocking↗
PubMed2006

Recurrent KRAS codon 146 mutations in human colorectal cancer.

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.

Adenocarcinoma↗
PubMed2006

Passive properties of the diaphragm in COPD.

Structural adaptations that occur in the diaphragm muscle of patients with chronic obstructive pulmonary disease (COPD), namely an increase in type I fibers and a decrease in type II fibers, have been explored in terms of the active contractile properties of the diaphragm. The aim of this study was to test the passive properties of the diaphragm by measuring the force response of relaxed diaphragm muscle fibers to stretching to determine the effect of COPD on these properties. Costal diaphragm biopsies were taken from patients with COPD and from controls with normal pulmonary function. From these biopsies, titin expression was assessed in diaphragm homogenates by gel electrophoresis, and the restoring force was measured by incremental stretching of single fibers in the relaxed state and measuring the force response to stretching. A quadratic model was used to illustrate the relationship between restoring force and muscle fiber length, and it revealed that COPD fibers generate significantly lower restoring forces than control fibers as judged by the area under the force-length curve. Furthermore, this finding applies to both type I and type II fibers. Gel electrophoresis revealed different titin isoforms in COPD and controls, consistent with the conclusion that COPD results not only in a change in muscle fiber-type distribution but in a structural change in the titin molecule in all muscle fiber types within the diaphragm. This may assist the muscle with the energetic changes in the length of the diaphragm required during breathing in COPD.

Adaptation, Physiological↗
PubMed2006

Abdominal compartment syndrome: a rare complication of plication of the diaphragm.

Abdominal compartment syndrome is an increasingly recognized phenomenon. We report the case of an otherwise fit and healthy 42-year-old man who underwent plication of the right hemidiaphragm for idiopathic phrenic paresis. His postoperative recovery was complicated by abdominal compartment syndrome, which was managed conservatively. We believe this is the only report of this complication after diaphragmatic plication and one of very few reported thoracic causes of abdominal compartment syndrome.

Abdomen↗
PubMed2006

A prospective, randomized, controlled trial of the effectiveness of BioGlue in treating alveolar air leaks.

OBJECTIVE: The use of tissue glues has been advocated to reduce post-thoracotomy alveolar air leaks, but outcomes have been inconclusive. The aim of this study was to determine the effectiveness of BioGlue (CryoLife Europa Ltd, Hampshire, United Kingdom) in eliminating post-thoracotomy alveolar air leaks. METHODS: A prospective, randomized, single-blind, controlled trial was conducted in which patients were stratified according to the severity of post-thoracotomy air leak that could not be controlled by conventional surgical techniques. They were allocated to a control arm (surgical treatment only) or an interventional arm (surgical treatment and BioGlue). Duration of air leak, intercostal drainage, and hospital stay comprised primary study end points. RESULTS: From December 2002 to January 2005, 52 patients were randomized, 29 (56%) of whom were men. The mean age was 59 +/- 15 years, and other characteristics were comparable in both groups. Indications for surgery were malignancy in 46 patients (88%), carcinoid tumor in 2 patients (4%), and infective disease in 4 patients (8%). Patients in the BioGlue arm had shorter median duration of air leaks, 1 (0-2) versus 4 (2-6) days (P < .001); intercostal chest drainage, 4 (3-4) versus 5 (4-6) days (P = .012); and hospital stay, 6 (5-7) versus 7 (7-10) days (P = .004), compared with controls. No major complications were encountered using BioGlue. CONCLUSIONS: This study demonstrates clear benefit from BioGlue in the treatment of alveolar air leaks through reduction of air leak duration, chest drainage time, and hospital stay. Systematic use of BioGlue may be warranted in adult thoracic surgical procedures (except pneumonectomy and decortication) when an air leak remains after all other steps to control it have failed.

Adult↗
PubMed2005

Nuss procedure improves the quality of life in young male adults with pectus excavatum deformity.

OBJECTIVE: The Nuss procedure is a minimally invasive pectus repair. This study represents an attempt towards exploring the changes in quality of life and overall satisfaction in young male adults who underwent a Nuss procedure. METHODS: We have included 20 male patients with a median age of 18 years (range: 14-37 years). We have used two specific questionnaires: the two-step Nuss evaluation Questionnaire modified for Adults (NQ-mA) and a new Single Step Questionnaire (SSQ). The data was analysed using Wilcoxon signed rank test to determine statistical significance of differences, with a <0.05 level of significance. Spearman's correlation coefficient was used to assess the correlation between the answers. RESULTS: The primary indication for surgery was cosmetic. Both questionnaires were adequate to measure disease-specific quality-of-life changes after surgery and were able to confirm the positive impact of surgery on both the physical and the physiological well-being of young adults. Statistical analysis of the scoring of the individual questions and the total score of individual patients revealed a statistically significant improvement (p<0.05) following surgery. The SSQ had a highly significant correlation to the NQ-mA questionnaire (correlation coefficient=0.682, p=0.001). Overall, the SSQ revealed a statistically significant improvement (p=0.001) in self-esteem and a high level of satisfaction following the Nuss procedure. Only two patients fell into a low satisfaction group. CONCLUSION: The Nuss procedure has already been shown to have a positive impact on both the physical and psychosocial well-being of children who are suffering from pectus excavatum deformity. We have shown a similar positive impact in young male adults, in the short term.

Adolescent↗
PubMed2005

Somatic mutations of the protein kinase gene family in human lung cancer.

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.

Adenocarcinoma↗
PubMed2005

Gene expression signature for angiogenic and nonangiogenic non-small-cell lung cancer.

Angiogenesis is regarded as essential for tumour growth. However, we have demonstrated that some other aggressive non-small-cell lung carcinomas (n-SCLC) do not have angiogenesis. In this study, using cDNA microarray analysis, we demonstrate that angiogenic and nonangiogenic tumour types can be distinguished by their gene expression profiles. Tissue samples from 42 n-SCLC patients were obtained with consent. In all, 12 tumours were nonangiogenic and 30 angiogenic. The two groups were matched by age, sex, smoking and tumour stage. Total RNAs were extracted followed by microarray hybridization and image scan procedure. Data were analysed using GeneSpring 5.1 software. A total of 62 genes were found to be able to separate angiogenic from nonangiogenic tumours. Nonangiogenic tumours have higher levels of genes concerned with mitochondrial metabolism, mRNA transcription, protein synthesis and the cell cycle. Angiogenic tumours have higher levels of genes coding for membrane vesicles, integrins, remodelling, angiogenesis and apoptosis. These results further support our first finding that nonangiogenic lung tumours are fast-growing tumours filling the alveoli in the absence of vascular remodelling. We raise the hypothesis that in nonangiogenic tumours, hypoxia leads to a higher activation of the mitochondrial respiratory chain, which allows tumour growth without triggering angiogenesis.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Somatic genetic changes accompanying lung tumor development.

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive process

Adult↗
PubMed2005

The impact of stage and cell type on the prognosis of pulmonary neuroendocrine tumors.

OBJECTIVE: In pulmonary neuroendocrine tumors the realization that the extent of nodal disease is related to cell type has led to a controversy as to which is the dominant prognostic factor, stage or morphology. To clarify this relationship, we studied patients treated at our institution over a 23-year period. METHODS: This is a historical cohort study of patients with confirmed pulmonary neuroendocrine tumors who underwent lung resection from 1980 through 2003. Survivors were contacted by telephone, and recurrences were confirmed by means of histopathology. Cox proportional hazards regression was used to ascertain the joint influence of several risk factors on survival. RESULTS: The mean age of the cohort was 54 years (standard deviation, 15 years), and 100 (57%) were men. The cell types for the 177 eligible patients were typical carcinoid in 89 (50%), atypical carcinoid in 15 (8%), large cell in 22 (13%), and small cell in 51 (29%). The median time to follow-up was 7 years (first to third quartile, 2-12 years), and overall 5- and 10-year survivals were 86% (79%-90%) and 81% (74%-87%), respectively. The univariable predictors of survival were age (P = .001), nodal stage (P = .01), and cell type (P < .001). In the final multivariable model only age (P = .04) and cell type (P < .001) remained as independent predictors. The hazard of death among patients with large cell or small cell lung cancer was highest in the first year and a half after diagnosis, reducing drastically thereafter. CONCLUSIONS: In pulmonary neuroendocrine tumors cell type is the predominant determinant of survival. The survival of patients with each cell type is sufficiently diverse to warrant different management strategies. Conservative resection is feasible for typical carcinoids, but the effects of adjuvant chemotherapy need to be evaluated for the other subgroups.

Cohort Studies↗
PubMed2005

Complete resection in lung cancer surgery: proposed definition.

OBJECTIVE: To propose an internationally accepted definition of complete resection in lung cancer surgery. MATERIAL AND METHODS: The International Association for the Study of Lung Cancer (IASLC) Staging Committee created the Complete Resection Subcommittee in 2001 to work on an international definition of complete resection in lung cancer surgery. The previous definitions of complete resection and the rules of the International Union Against Cancer regarding the TNM residual tumor classification, together with a thorough review of the pertinent literature, and the input of the members of the IASLC Staging Committee were considered in order to get an international consensus on the definition of complete resection in lung cancer surgery. RESULTS: Complete resection requires all of the following: free resection margins proved microscopically; systematic nodal dissection or lobe-specific systematic nodal dissection; no extracapsular nodal extension of the tumor; and the highest mediastinal node removed must be negative. Whenever there is involvement of resection margins, extracapsular nodal extension, unremoved positive lymph nodes or positive pleural or pericardial effusions, the resection is defined as incomplete. When the resection margins are free and no residual tumor is left, but the resection does not fulfill the criteria for complete resection, there is carcinoma in situ at the bronchial margin or positive pleural lavage cytology, the term uncertain resection is proposed. CONCLUSION: The proposed definitions of complete, incomplete and uncertain resections are clear and reproducible in an international setting to study their prognostic impact prospectively.

Humans↗