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P Hasleton

Publications and source records attributed to P Hasleton.

At least 19 recordsLinked to original sources
PubMed2006

Sensitivity and specificity of immunohistochemical antibodies used to distinguish between benign and malignant pleural disease: a systematic review of published reports.

AIMS: A systematic review of published reports that have evaluated the ability of immunohistochemistry and argyrophil nucleolar organizing region (AgNOR) staining to distinguish between benign and malignant pleural disease. METHODS: Nineteen relevant papers published during the period 1979-2005 were identified. Individual results of immunohistochemistry for five diagnostic antibodies were extracted to calculate diagnostic sensitivity and specificity. results from five of these studies that had evaluated proliferation markers or AgNOR staining techniques were also summarized. RESULTS: Most antibodies demonstrated poor to moderate diagnostic ability. Desmin and epithelial membrane antigen (EMA) were the most useful, with sensitivity and specificity both above 74%. The combination of EMA and AgNOR was reported as having 95% diagnostic sensitivity. A high MCM2 labelling index also differentiated between benign and malignant pleural disease. CONCLUSIONS: Immunohistochemistry is of limited value, but newer diagnostic methods may be useful additions in this area of pathology. The diagnostic importance of histological features seen on plain tissue sections is emphasized as vital for correctly differentiating between benign pleural disease and malignant pleural mesothelioma.

Antigens, Neoplasm↗
PubMed2001

Transforming growth factor beta and myocardial dysfunction following heart transplantation.

OBJECTIVE: We analyzed the role of transforming growth factor-beta (TGF-beta), a fibrogenic cytokine, in the development of left ventricular diastolic dysfunction following heart transplantation. METHODS: We studied 152 heart transplant recipients who had survived for at least 24 months. We compared histopathological findings (staining of endomyocardial biopsy specimens using Hematoxylin Eosin and polyclonal antibodies), left ventricular function (Doppler echocardiography) and clinical course (NYHA status). Patients are classified into group A (n=56 recipients) with immunohistochemical TGF-beta staining score >7 and group B (n=96 recipients) with a staining score <7. RESULTS: Doppler echocardiographic evaluation demonstrated greater impairment of left ventricular diastolic function in recipients with higher TGF-beta staining score. The average mitral deceleration time was 129+/-6 ms for recipients group A compared to 167+/-15 ms in group B. While the mean isovolumic relaxation time was 65+/-8 ms for patients in group A compared with 82+/-6 ms for recipients in group B (P=0.0004 and 0.005, respectively). Immunohistochemical scoring correlated inversely with both mitral deceleration and isovolumic relaxation times (r=-0.74, P=0.0004 and r=-0.66, P=0.004, respectively). Mean NYHA status was 2.7+/-1.3 for group A compared to 1.17+/-0.4 in group B was (P=0.002). Five years follow-up revealed persistent left ventricular diastolic impairment for recipients with higher immunohistochemical staining score. Mitral deceleration time and isovolumic relaxation time were 118+/-11 and 62+/-7 ms for group A compared to 156+/-12 and 80+/-5 ms for group B, P=0.006 and P=0.01, respectively. The actuarial development of subsequent coronary artery disease (> 50% stenosis) was 17 and 29% for recipients in group A compared to 4 and 6% for recipients in group B at 3 and 5 years follow-up, respectively (P=0.01 and P=0.005, respectively). CONCLUSIONS: TGF-beta expression in cardiac allografts is associated with impaired graft function and limited survival. The pathogenesis of diastolic dysfunction may be an aberrant repair process following rejection due to increased TGF-beta expression in transplant recipients.

Biopsy↗
PubMed2000

Transforming growth factor beta in relation to cardiac allograft vasculopathy after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy is a frequent sequel to cardiac transplantation, but the role of cytokines on the subsequent development of vasculopathy is still largely unknown. METHODS: We retrospectively studied 172 heart transplant recipients to investigate the relationship between the development of vasculopathy and various factors including the presence of transforming growth factor (TGF-beta) in the graft. Endomyocardial biopsy specimens were stained with antibodies for TGF-beta and CD+68, and a TGF-beta staining score was derived. Vasculopathy was diagnosed by angiography and rejection was graded according to the International Society of Heart and Lung Transplantation classification. TGF-beta(1) genotype was determined by polymerase chain reaction analysis of DNA. RESULTS: After a mean follow-up period of 68 +/- 32 months, the prevalence of significant vasculopathy was 52%. The TGF-beta staining score was higher in patients with more severe vasculopathy (95% confidence interval = 8.9-12.1) than in those who showed minimal or mild vasculopathy score changes of more than 7 (95% confidence interval = 3.4-5.1), P =.0001. TGF-beta expression correlated with the degree of vasculopathy (r = 0.73, P <.0007) during the study period. Risks for vasculopathy were recipient homozygous TGF-beta genotype, recurrent rejection, recipient history of ischemic heart disease, donor male sex, old donor age (years), and donor history of subarachnoid hemorrhage. CONCLUSION: A strong association exists between the expression of TGF-beta in cardiac biopsy specimens and the development of vasculopathy. TGF-beta in the cardiac allograft is related to its genotype and to the number of rejection episodes. Strategies to down-regulate TGF-beta production might improve the outcome of cardiac allografts.

Adult↗
PubMed2000

Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours.

Human bronchioloalveolar carcinoma (BAC) is a lung cancer, morphologically similar to an endemic contagious lung neoplasm of sheep called sheep pulmonary adenomatosis (SPA) or jaagsiekte. SPA is caused by an exogenous type B/D retrovirus (jaagsiekte sheep retrovirus (JSRV)), which prompted the present study to obtain evidence of a retrovirus in BAC. A panel of 249 human lung tumours, 21 nontumour lung lesions, four normal lung tissues, 23 adenocarcinomas from other organs and a cell line expressing a human endogenous retrovirus protein was examined immunohistochemically using a rabbit antiserum directed against the JSRV capsid protein. Specific staining was detected only in the cytoplasm of recognizably neoplastic cells in the pulmonary alveoli of 39 of 129 (30%) BACs, 17 of 65 (26%) lung adenocarcinomas and two of seven large cell carcinomas. The remaining samples were negative. These results support the hypothesis that some human pulmonary tumours may be associated with a jaagsiekte sheep retrovirus-related retrovirus, warranting further studies.

Adenocarcinoma↗
PubMed2000

Pulmonary atypical carcinoid: predictors of survival in 106 cases.

Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.

Adult↗
PubMed2000

[Expression of transforming growth factor beta 1 (TGF beta 1) and angiogenesis in broncho-pulmonary carcinoids].

TGF beta 1 commonly produced by normal and neoplastic human cells, has capacity to regulate new blood vessel formation, to establish and maintain the vessel wall integrity; was found to have some significance in the lung cancer prognosis. Tumour angiogenesis is an important factor for tumour growth and metastasis. The purpose of this study was to find, if the immunoexpression of TGF beta 1 has any significance in determination of the histologic subtypes of carcinoids?; to find, if TGF beta 1 has any role and relation to carcinoids angiogenesis?; and to explore TGF beta 1 expression and angiogenesis with respect to metastatic potential of carcinoids. The study was performed on 48 resected broncho-pulmonary carcinoids: 35 typical (TC) and 13 atypical (AC), classified according to the WHO. Semiquantitative analysis for TGF beta 1 was performed. Sections stained using monoclonal antibody against TGF beta 1 were scored in scale from 0 to 4, according to the percentage of positively stained cells (pc) plus percentage of positively stained stroma (ps). The microvessels stained with CD34 monoclonal antibody, were counted in 0.75 mm2 field (microvessel density--MD), using the computerised image analysis system SAMBA 2005 (the morphometric software). The histologic subtype of carcinoids was related to age of the pts (AC occurred in older pts than TC, p = 0.027), to the tumour size (AC were larger than TC: respectively--3.25 cm and 2.4 cm, p = 0.009). Lymph node metastases were significantly more frequent in AC than in TC (38% vs 13%, p = 0.025). 85% carcinoids showed TGF beta 1 expression with various intensity, mainly in the stroma. There was no significant correlation between TGF beta 1 expression and tumour size, the histologic subtype nor the lymph node metastases. The angiogenesis expressed as MD, was not related to histology, nor to the presence of lymph node metastases. There was no correlation between TGF beta 1 expression and angiogenesis. Shown in our study, lack of relation between TGF beta 1 expression and angiogenesis, could support some of the published data indicating indirect action of TGF beta 1 on the angiogenesis. The rich vascularity found in carcinoids morphology could result from TGF beta 1, commonly expressed by the tumoural stroma. The angiogenesis nor TGF beta 1 expression do not determinate the carcinoids histology.

Adult↗
PubMed1999

Genetic changes in the spectrum of neuroendocrine lung tumors.

BACKGROUND: Recent classifications identify four categories of neuroendocrine (NE) tumors of the lung: low grade typical carcinoid (TC), intermediate grade atypical carcinoid (AC), and high grade large cell neuroendocrine carcinoma (LC-NEC) and small cell lung carcinoma (SCLC). METHODS: The authors studied the molecular changes present in 59 archival NE tumors (10TCs, 11 ACs, 18 LNECs, and 20 SCLCs). Utilizing microdissection and polymerase chain reaction-based assays, the authors examined loss of heterozygosity (LOH) at ten chromosomal regions frequently deleted in lung tumors (3p, 5q, 11q, 13q, and 17p) and for mutations at the p53 and ras genes. RESULTS: With the exception of ras gene mutations, the majority of these changes frequently were present in carcinomas and were present at lower frequencies in carcinoids. LOH at one or more 3p regions was the most frequent change found in the carcinoids. A relatively high incidence of LOH at the MEN1 gene was common in all NE lung tumors. The incidence of LOH and p53 gene abnormalities progressively increased with increasing severity of tumor type. The patterns of p53 gene mutations were different between AC and high grade NE tumors. LOH at 5q21 was correlated with poor survival in the carcinoid group. CONCLUSIONS: Although NE lung tumors have varied etiologies, the results of the current study support the clinicopathologic concept that they represent a spectrum ranging from low grade TC to the highly malignant NE carcinomas.

Carcinoid Tumor↗
PubMed1999

Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation.

BACKGROUND: Obliterative bronchiolitis (OB) characterised by small-airway fibrosis is a major cause of morbidity and mortality after lung transplantation. TGF-beta has been implicated in the pathogenesis of fibrosis. METHODS: We immunohistochemically examined 380 transbronchial biopsies (from 91 pulmonary transplants) using TGF-beta polyclonal antibodies. OB and interstitial fibrosis were diagnosed and graded in all biopsies. Other potential histologic and clinical risk factors for OB were analysed. RESULTS: Procedures were heart and lung (n = 32), bilateral sequential lung (n = 18), and single lung transplantation (n = 41). The incidence of OB in this group was 28.5%. In all patients with OB, TGF-beta was immunolocalized in the airways and lung parenchyma. TGF-beta expression was greater in OB patients (median score 8, range 5-12) in comparison to patients without OB (median score 4, range 1-13), p < .0001. Positive TGF-beta staining preceded the histologic confirmation of OB by 6 to 18 months. The development of OB was associated with two HLA mismatches at the A locus (p = .02); recurrent acute rejection episodes (p < .0005); lymphocytic bronchiolitis (p = .0001); and tissue eosinophilia, regardless of the rejection grade (p < .0001). CONCLUSIONS: Increased expression of TGF-beta is a risk factor for the development of OB. Other risk factors are recurrent acute rejection, lymphocytic bronchiolitis, tissue eosinophilia, and two mismatches at the HLA-A locus. This suggests that the pathogenesis of progressive small airway fibrosis characteristic of OB may be inflammatory damage, followed by an aberrant repair process due to excessive TGF-beta production following allograft injury. Hence, modulation of TGF-beta levels or function by antagonists may represent an important approach to control OB.

Adult↗
PubMed1998

Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation.

BACKGROUND: Transforming growth factor (TGF)-beta1 is a profibrogenetic cytokine that has been implicated in the development of fibrosis in transplanted tissues. In this study, we have analyzed the genetic regulation of TGF-beta1 production in lung transplant recipients. METHOD: A polymerase chain reaction-single-stranded conformational polymorphism technique was used to detect polymorphisms in the TGF-beta1 gene from genomic DNA. Polymorphisms were shown to correlate with in vitro TGF-beta1 production by stimulated lymphocytes. A single-specific oligonucleotide probe hybridization method was devised to screen for these polymorphisms in lung transplant groups and controls. RESULTS: We have identified five polymorphisms in the TGF-beta1 gene: two in the promoter region at positions -800 and -509, one at position +72 in a nontranslated region, and two in the signal sequence at positions +869 and +915. The polymorphism at position +915 in the signal sequence, which changes codon 25 (arginine-->proline), is associated with interindividual variation in levels of TGF-beta1 production. Stimulated lymphocytes of homozygous genotype (arginine/arginine) from control individuals produced significantly more TGF-beta1 in vitro (10037+/-745 pg/ml) compared with heterozygous (arginine/proline) individuals (6729+/-883 pg/ml; P<0.02). In patients requiring lung transplantation for a fibrotic lung condition, there was an increase in the frequency of the high-producer TGF-beta1 allele (arginine). This allele was significantly associated with pretransplant fibrotic pathology (P<0.02) (n=45) when compared with controls (n=107) and with pretransplant nonfibrotic pathology (P<0.004) (n=50). This allele was also associated with allograft fibrosis in transbronchial biopsies when compared with controls (P<0.03) and with nonallograft fibrosis (P<0.01). CONCLUSION: The production of TGF-beta1 is under genetic control, and this in turn influences the development of lung fibrosis. Hence, the TGF-beta1 genotype has prognostic significance in transplant recipients.

Alleles↗
PubMed1998

Transforming growth factor-beta1 and lung allograft fibrosis.

OBJECTIVES: Transforming growth factor beta1 (TGF-beta1) is a potent immunosuppressive cytokine that promotes fibrosis by enhancing the synthesis of extracellular matrix components. The repair process following lung allograft injury is due to rejection or infection replaces lung parenchyma by fibrotic tissue, leading to pulmonary dysfunction. The role of TGF-beta1 in this excessive healing process and increasing the risk of infection is unknown. METHODS: We analysed our patient data to investigate the relevance of different factors on allograft fibrosis and its correlation with TGF-beta1. Fibrosis was graded in H and E stained sections. TGF-beta1 genotype was determined in all patients. RESULTS: Patients were aged between 16 and 62 years (mean age of 39.6 years). Procedures were heart/lung (n = 32), double lung (n = 18), and SLT (n = 41). A total of 46 patients had lung allograft fibrosis diagnosed in transbronchial biopsies sections. Patients who had developed interstitial fibrosis had significantly more acute rejection episodes (mean 3.4 +/- 2.8) compared with patients without fibrosis (mean 2.1 +/- 2.2) (P = 0.024). The presence of eosinophils in the interstitium preceded and were associated with the development of fibrosis regardless of the rejection grade (P = 0.0001). TGF-beta1 was heavily expressed in sections with fibrosis with a mean score of 6.8 +/- 2.9 compared with 2.4 +/- 0.6 in sections with no fibrosis (P < 0.0001). TGF-beta1 expression correlated positively with fibrosis grades (P < 0.0001). The mean survival for patients with a fibrosis score > 6 is 892.4 +/- 73 days compared with mean survival 427 +/- 78 in patients with scores < 6 (P = 0.0001). Patients who developed fibrosis had homozygous TGF-beta1 genotype that correlates with excessive TGF-beta1 expression (P = 0.01). The use of cardiopulmonary bypass was associated with the development of excessive fibrosis (P = 0.02), and 7 patients who had severe fibrosis died of septicaemia (17.5%). FEV1 (forced expiratory volume) was significantly higher in patients without fibrosis (1870 +/- 111 ml versus 1590 +/- 160; P = 0.02). CONCLUSIONS: The risks of lung allograft fibrosis increases with recurrent rejection, tissue eosinophilia, homozygous TGF-beta1 genotype and the use of bypass machine. Fibrosis was associated with higher mortality and morbidity might be explained by the TGF-beta1 immunosuppressive and fibrotic properties. Immunological strategies to down-regulate TGF-beta1 production might improve survival and function of lung allografts.

Adolescent↗
PubMed1996

Clonal evolution of lung tumors.

Lung tumors, particularly squamous cell carcinomas, are believed to develop through a series of morphological abnormalities, driven by underlying somatic genetic changes. One way of studying this process is to analyze candidate somatic genetic changes in samples of squamous metaplasia and bronchial dysplasia of varying degrees of severity as well as tumor from the same patient. This assumes a clonal relationship between these lesions. In this article, we provide evidence that adjacent, physically distinct bronchial abnormalities are clonally related. This has been achieved using a plaque assay technique to detect the same p53 mutation, present throughout a tumor specimen, in a small proportion of cells in an adjacent squamous metaplasia. In addition, we have obtained two dysplasia samples from a tumor-free patient over a 9-month interval. The earlier sample had one p53 mutation, whereas the later sample has to p53 mutations on different alleles. Thus, the pattern of clonal evolution detected in the parallel samples mimics the pattern seen in longitudinal samples and supports the analysis of synchronously collected samples for the study of tumor progression.

Base Sequence↗
PubMed1995

Sequential molecular genetic changes in lung cancer development.

Epithelial tumours develop through a sequence of pre-invasive lesions of increasing disarray driven by underlying somatic genetic changes. We have studied the occurrence of the two most common somatic genetic changes associated with lung cancer in a series of premalignant bronchial lesions representing different stages in lung tumorigenesis. We present evidence that allele loss on chromosome 3 precedes damage to the p53 gene. Damage to chromosome 3 itself appears to be sequential in that the pattern of allele loss seen in dysplasia is often much more discrete than in invasive tumours. This implies that preneoplastic lesions may be a useful source of material for deletion mapping studies aimed at localising the position of tumour suppressor genes. We illustrate this by the comparison of an interstitial deletion described in this study with a homozygous deletion we have described previously, which has resulted in a better definition of the localisation of a tumour suppressor gene believed to be involved in lung cancer development.

Base Sequence↗
PubMed1995

Somatic genetic changes in lung cancer and precancerous lesions.

BACKGROUND: Morphological abnormalities of the bronchial epithelium are associated with lung cancer development and are considered likely to represent the preneoplastic stage of the disease. The association of these lesions with different histological types of lung cancer was reviewed in a series of 97 samples. Lesions associated with squamous cell carcinomas provided the best samples for further study. The objective of this study was to describe the somatic genetic changes which occur in these preinvasive lesions. Among the various candidate somatic genetic changes, loss of heterozygosity on chromosome 3 and changes to the p53 gene were selected as being the most informative. It was demonstrated that these genetic changes, characteristic of fully invasive lung tumours, also occur at the premalignant stage of the disease. In an attempt to take a less directed approach to the comparison of invasive and preinvasive lesions, karyotype analysis was performed on short-term cultures of bronchial cells adjacent to the bronchial margin obtained from patients undergoing lung tumour resection. One such karyotype had a deletion to chromosome 3 (del 3p13-14) as the single abnormality. CONCLUSION: It was concluded that genetic damage to p53 and chromosome 3 is involved in the preinvasive stage of lung cancer, and that damage to chromosome 3 is a particularly early event.

Bronchi↗
PubMed1993

Paraffin wax-embedded material as a source of DNA for the detection of somatic genetic changes.

Loss of genetic material, corresponding to chromosomal deletions, has been detected in a wide range of tumours and may indicate the position of a tumour suppressor gene. In order to identify the position of such a gene more precisely, many tumour samples must be studied until a minimum consensus deletion is characterized. This process is particularly necessary for lung tumours in which the deletion in chromosome 3, seen with such high frequencies in all histological subtypes, is almost always large. We have recently described the use of the polymerase chain reaction (PCR) for restriction fragment length polymorphism (RFLP) analysis of DNA isolated from small bronchial biopsies of lung tumours. In this study we adapted this technique to allow genotyping of DNA isolated from paraffin wax-embedded material (PWEM) microdissected from glass slides. We have investigated 12 lung tumours at polymorphic loci on chromosome 3 and showed allelic loss in all samples. In adapting PCR-RFLP analysis for DNA isolated from PWEM, we have concentrated on those approaches which might be adaptable to routine clinical practice. Somatic genetic changes are now being identified in many tumour types, and this information is expected to be of diagnostic and prognostic significance.

Alleles↗
PubMed1992

p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus.

Bronchial epithelial dysplasia is believed to precede invasive squamous cell carcinoma of the lung. Six paired dysplasia and tumour samples were distinguished histologically in sections of formalin-fixed paraffin-embedded lung tissue from patients with lung cancer. Additionally, samples of dysplastic bronchial epithelium were obtained from patients without lung tumours. Microdissection of the unstained sections provided dysplastic and tumour samples from which DNA was prepared for comparison with the patients' constitutional genotype, using polymerase chain reaction-based restriction fragment length polymorphism analysis. All six samples of tumour and the paired adjacent samples of bronchial dysplasia showed loss of heterozygosity (LOH) at loci on the short arm of chromosome 3. Five of the six cases showed involvement of the p53 gene as assessed by LOH at the AccII site within the gene, and by immunoreactivity to CM-1, an antibody which recognizes the mutated form of the p53 protein in paraffin-embedded material. Of the dysplastic samples, obtained from patients without invasive tumours, all three showed LOH at 3p; one sample showed LOH at the AccII polymorphic locus within the p53 gene, and another sample, uninformative at this locus, stained positively with this antibody. These results indicate that somatic genetic changes are present in preinvasive lesions in the bronchus.

Base Sequence↗