Interstitial fibrosis in the dilated non-ischaemic myocardium.
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Adult↗
Biomedical subjects
A C Bateman
Publications and source records attributed to A C Bateman.
BAG-1 expression and function in human cancer.
BAG-1 is a multifunctional protein that interacts with a wide range of target molecules to regulate apoptosis, proliferation, transcription, metastasis and motility. Interaction with chaperone molecules may mediate many of the effects of BAG-1. The pathways regulated by BAG-1 play key roles in the development and progression of cancer and determining response to therapy, and there has been considerable interest in determining the clinical significance of BAG-1 expression in malignant cells. There is an emerging picture that BAG-1 expression is frequently altered in a range of human cancers relative to normal cells and a recent report suggests the exciting possibility that BAG-1 expression may have clinical utility as a prognostic marker in early breast cancer. However, other studies of BAG-1 expression in breast cancer and other cancer types have yielded differing results. It is important to view these findings in the context of current knowledge of BAG-1 expression and function. This review summarises recent progress in understanding the clinical significance of BAG-1 expression in cancer in light of our understanding of BAG-1 function.
Apoptosis↗
Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma.
Vascular endothelial growth factor (VEGF) is a potent regulator of vasculogenesis and tumour angiogenesis. We have investigated whether the VEGF -2578, -1154, +405 and +936 SNPs and associated haplotypes confer susceptibility to and/or influence prognosis in cutaneous malignant melanoma (CMM) skin cancer. A total of 152 CMM patients and 266 controls were genotyped for VEGF promoter SNPs by ARMS-PCR. Strong linkage disequilibrium between the -2578, -1154 and +405 SNPs was detected (association, rho = 0.488-0.965), but not between these SNPs and SNP +936 (association, rho = 0.004-0.130). No SNPs or three SNP haplotypes (-2578, -1154, +405) were significantly associated with CMM, although a number of non-significant trends were observed. However, the VEGF -1154 AA genotype and -2578, -1154, +405 CAC haplotype were both significantly associated with less advanced (Stage 1) disease (P = 0.03). In addition, the VEGF -1154 AA genotype was associated with thinner primary vertical growth phase tumours (P = 0.002), while VEGF -1154 GG was associated with thicker primary tumours (P = 0.02). These preliminary results indicate that VEGF genotype may influence tumour growth in CMM, possibly via the effects of differential VEGF expression on tumour angiogenesis.
Endothelial Growth Factors↗
Influence of TNFalpha and LTalpha single nucleotide polymorphisms on susceptibility to and prognosis in cutaneous malignant melanoma in the British population.
Cutaneous malignant melanoma (CMM) is a potentially fatal malignancy in which exposure to UV light is the most important risk factor. Several lines of evidence suggest that increased expression of tumour necrosis factor (TNF) alpha, upregulated by UV exposure, may contribute to tumour escape from the immune response. In this study, we addressed whether single nucleotide polymorphisms (SNPs) in the TNFalpha promoter and lymphotoxin (LT) alpha gene are associated with susceptibility to or known prognostic indicators (e.g. initial tumour growth phase, Breslow thickness, mitotic count in vertical growth phase tumours, and tumour regression) in CMM. One hundred and forty-six British Caucasian CMM patients and 220 controls were typed for TNFalpha-376, -308 and -238 and LTalpha+252 SNPs by ARMS-PCR. Only the TNFalpha -238 GG (P = 0.05) and GA (P = 0.03) genotypes showed slight, but significant, associations with CMM, while LTalpha+252 AA was associated with a higher mitotic count in vertical growth phase tumours (P = 0.02). Both TNFalpha-238 and LTalpha+252 SNPs showed linkage disequilibrium with HLA-DQB1*0303 and *0301 alleles, variably implicated in CMM susceptibility/prognosis. In addition, TNFalpha-238, -308, LTalpha+252 haplotypes were assigned and compared. The GGA haplotype showed a modest association with CMM (P = 0.04) and with stage of disease (P = 0.03) and initial growth phase in CMM (P = 0.02), but these associations were only significant when P-values were uncorrected. Unlike basal cell carcinoma, these preliminary findings suggest that genetic variation associated with differential TNFalpha and LTalpha production is unlikely to play a major, independent role in susceptibility to, and perhaps prognosis in, CMM.
Case-Control Studies↗
An insight into the genetic pathway of adenocarcinoma of the small intestine.
BACKGROUND: Although the adenoma to carcinoma pathway in colorectal cancer is well described, the mechanisms of carcinogenesis in the small intestine remain unclear. AIMS: The aim of this study was to investigate candidate genes in the genetic pathway of adenocarcinoma of the small intestine. SUBJECTS AND METHODS: A total of 21 non-familial, non-ampullary adenocarcinomas of the small intestine were analysed. DNA was extracted from formalin fixed paraffin wax embedded tissue using standard techniques. The replication error (RER) status was determined by amplification of BAT26. The mutation cluster region (MCR) of the adenomatous polyposis coli (APC) gene was screened using polymerase chain reaction single strand conformational polymorphism and direct sequencing. Immunohistochemistry was performed on formalin fixed paraffin wax embedded tissue using monoclonal antibodies for hMLH1, hMSH2, beta-catenin, E-cadherin, and p53. RESULTS: Fourteen male and seven female patients with a median age of 64 years (range 21-85) presented with adenocarcinoma of the duodenum (10), jejunum (7), and ileum (4). One cancer (5%) was found to be RER+, and all tumours stained positive for hMLH1 and hMSH2. No mutations were detected in the MCR of the APC gene. beta-Catenin showed increased nuclear expression with loss of membranous staining in 10 cancers (48%). Absent or decreased membrane expression of E-cadherin was found in eight cancers (38%). Strong staining of p53 was found in the nucleus of five cancers (24%). CONCLUSION: We did not detect mutations in the MCR of the APC gene, and this suggests that adenocarcinoma of the small intestine may follow a different genetic pathway to colorectal cancer. Abnormal expression of E-cadherin and beta-catenin was common and reflects an early alternative to APC in this pathway in which mutations may be found in adenocarcinoma of the small intestine.
Adaptor Proteins, Signal Transducing↗
Apoptosis and proliferation of acinar and islet cells in chronic pancreatitis: evidence for differential cell loss mediating preservation of islet function.
BACKGROUND: Chronic pancreatitis is characterised clinically by early exocrine insufficiency, with diabetes mellitus occurring as a late phenomenon. This is mirrored pathologically by extensive acinar cell destruction and islet preservation. The mechanisms underlying this differential rate of cellular destruction are unknown. AIMS: To test the hypothesis that acinar loss and islet preservation in chronic pancreatitis occurs due to differential epithelial kinetics and investigate the role of inflammatory cells and cell cycle associated molecules. METHODS: Archival tissue from six chronic pancreatitis cases was compared with six normal controls using TUNEL and immunohistochemistry for CD3, CD20, CD68, MIB-1, Bcl-2, Bax, Fas, Fas ligand, retinoblastoma protein (Rb), and tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2). RESULTS: The acinar cell apoptotic index (AI) and proliferation index were higher in chronic pancreatitis than controls. T lymphocytes diffusely infiltrated fibrous bands and acini but rarely islets. Acinar Bcl-2 expression exceeded islet expression in chronic pancreatitis and controls while Bax was strongly expressed by a subset of islet cells and weakly by centroacinar cells. Islet Fas and Fas ligand expression exceeded acinar expression in chronic pancreatitis and controls. Acinar Rb expression was higher in chronic pancreatitis than in controls. Islets in chronic pancreatitis and controls showed intense TIMP-1 and TIMP-2 expression. CONCLUSION: Apoptosis plays a significant role in acinar loss in chronic pancreatitis. Acinar Bcl-2 and islet Bax expression indicates complex AI control. Increased acinar Rb expression in chronic pancreatitis may differentially promote acinar loss. Fas ligand expression may be restricted to islet cell membranes through TIMP-1 expression and inhibit islet damage by promoting apoptosis of cytotoxic T lymphocytes.
Apoptosis↗
Massive hepatosplenomegaly caused by Penicillium marneffei associated with human immunodeficiency virus infection in a Thai patient.
A 29 year old Thai woman presented with non-specific features and examination revealed left upper zone consolidation and hepatosplenomegaly. The initial clinical differential diagnosis included tuberculosis and melioidosis. She died four days after admission, while still under investigation. Postmortem examination revealed antibodies to human immunodeficiency virus, disseminated Penicillium marneffei infection, and Salmonella enteritidis infection. Penicillium marneffei is a well described AIDS defining pathogen in South East Asia but is very rare in the UK. Appropriate antifungal treatment may be associated with a successful outcome. Increased awareness of this clinical association may enable correct diagnosis in affected patients from South East Asia presenting within the UK.
AIDS-Related Opportunistic Infections↗
BAG-1 immunostaining and survival in early breast cancer.
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Breast Neoplasms↗
Invasiveness of cutaneous malignant melanoma is influenced by matrix metalloproteinase 1 gene polymorphism.
The matrix metalloproteinases (MMPs) are implicated in connective tissue destruction during cancer invasion and metastasis. A naturally occurring variant arising from the insertion or deletion of a guanine in the promoter of the MMP-1 gene has recently been reported and shown to influence its transcriptional activity in melanoma cells. In this study, MMP-1 genotype was determined in 139 Caucasian patients with cutaneous malignant melanoma. The insertion allele was associated with deep invasive, and therefore poorer-prognosis, primary tumors [(34% of patients with vertical growth phase tumor were homozygous for the insertion allele compared with 17% of patients with horizontal growth phase tumor (P = 0.0333; odds ratio = 2.51)]. These data suggest that the invasiveness of cutaneous malignant melanoma is influenced by variation in the MMP-1 gene promoter that affects MMP-1 expression.
Cell Division↗
IL-10 promoter polymorphisms influence tumour development in cutaneous malignant melanoma.
Cutaneous malignant melanoma (CMM) is the most serious cutaneous malignancy. CMM patients often develop an immune response to their tumours. Conflicting evidence suggests that IL-10 may contribute to tumour escape from the immune response, but may also have an anti-tumour effect. To distinguish between these models and to determine whether genotypes associated with differential IL-10 expression confer susceptibility to and/or influence prognosis in CMM, 165 CMM patients and 158 controls were genotyped for IL-10 promoter SNPs by ARMS-PCR. The IL-10--1082 AA low expression genotype was increased in incidence among CMM patients (P = 0.04). In addition, IL-10 genotypes showed significant associations with three of four prognostic indicators examined; IL-10--1082 GG (P = 0.02) and -1082, -819 and -592 compound high expression (P = 0.03) genotypes were associated with horizontal (non-invasive) tumour growth; IL-10--1082 AA low expression genotype was associated with more advanced (Stage II-IV) disease (P = 0.04); finally, the IL-10--1082 AA (P = 0.005) and compound low expression (P = 0.009) genotypes were significantly increased in frequency among patients with thicker primary Vertical growth phase tumours. These results indicate that genotypes associated with high levels of IL-10 expression in vitro are protective in CMM, while low expression genotypes are a risk factor for more advanced/poorer prognosis disease and may confer susceptibility to CMM. Although the influence of IL-10 on melanoma development is likely to be complex, these results support recent findings that IL-10 has an anti-tumour effect in CMM, possibly via inhibition of angiogenesis.
Base Sequence↗
Oncofetal fibronectin and oral squamous cell carcinoma.
Fibronectin is a cell matrix glycoprotein, which exists as a number of isoforms that are often found within the cell matrix that surrounds tumours. Collectively these tumour-associated isomers of fibronectin have been termed oncofetal fibronectin (OFFN). We looked for expression of OFFN within oral squamous cell carcinomas (SCC) and related its presence to prognosis. The investigation used a monoclonal antibody (MoAb 5C10) to the glycosylated variant of OFFN, and 100 archival specimens of oral SSC. Immunostaining for OFFN was intense in the adjacent stroma of 43 squamous carcinomas, weak in 27 and absent in 30. Cervical metastases were found in 17/27 (63%) specimens that stained intensely, 6/17 (35%) that stained weakly and 3/13 (23%) that did not stain. Of the 21 cases which had extracapsular lymph node spread, 81% were from those that stained intensely, 19% from those that stained weakly and none from those that did not stain for OFFN expression. Also, 21/44 patients (49%) died in group with intense OFFN staining, 6/26 (23%) in the group with weak staining and 3/30 (10%) in the group that did not stain. The presence of OFFN glycoprotein in oral SCC as evaluated by immunostaining with MoAb 5C10 correlates strongly with the presence of metastatic lymph node involvement, particularly extracapsular involvement, and mortality. We therefore suggest that the degree of expression of OFFN in tumours is a valuable prognostic indicator.
Biomarkers, Tumor↗
The role and histological classification of needle core biopsy in comparison with fine needle aspiration cytology in the preoperative assessment of impalpable breast lesions.
AIMS: To investigate the role of needle core biopsy (NCB) in the preoperative assessment of impalpable breast lesions, mainly derived from the NHS Breast Screening Programme (NHSBSP) and to assess our own modifications to a suggested system for the classification of breast NCBs. METHODS: The NCB, fine needle aspiration cytology (FNAC), and radiology scores from 298 women with non-palpable breast lesions presenting between January 1997 and December 1998, together with the open biopsy results (where available) were collated and analysed. RESULTS: The mean follow up period was 15.8 months (range, 5-28). The 298 NCB specimens were categorised as follows: unsatisfactory/non-representative (B1; n = 61; 20.5%), benign but uncertain whether representative (B2r; n = 52; 17.4%), benign (B2; n = 103; 34.6%), lesions possibly associated with malignancy but essentially benign (B3a; n = 9; 3.0%), atypical epithelial proliferations (B3b; n = 10; 3.4%), suspicious of malignancy (B4; n = 7; 2.3%), and malignant (B5; n = 56; 18.7%). Excision biopsy was performed in 43 cases within the B1 (n = 19), B2r (n = 8), B2 (n = 8), and the B3a (n = 8; data unavailable in one case) categories, revealing malignancy in 18 (42.8%) cases and in 65 cases within the B3b, B4, and B5 categories, revealing malignancy in 64 cases (98.5%). The sensitivity of NCB for malignancy was 87.7%, with a specificity and positive predictive value of 99.3% and 98.5%, respectively. FNAC had an inadequacy rate of 58.7%, a complete sensitivity of 34.5% and a specificity of 47.6%. CONCLUSIONS: This study confirms the value of NCB in the preoperative assessment of impalpable breast lesions. Two new categories are suggested for the NCB classification; category B2r for benign breast tissue where representativeness is uncertain, and the subdivision of category B3 into B3a for benign lesions potentially associated with malignancy (for example, radial scars and intraduct papillomas) and B3b for more worrisome atypical epithelial proliferations. These will aid the accurate audit of NCB and identify more clearly the intellectual pathway leading to a particular assessment.
Aged↗
Predominant fatty variant of myofibroblastoma of breast.
Myofibroblastoma of the breast is an uncommon but well defined benign stromal tumour. This report describes a case in which the predominant histological component was mature adipose tissue and two further cases with a major adipocytic component. Although small foci of adipose tissue are a recognised feature of this tumour, the dominance of the histological pattern by fat has not been described previously, and the recognition of this variant is important to allow confident diagnosis and avoid confusion with other primary adipocytic or stromal lesions, especially in the setting of potential needle core biopsy of such a lesion.
Adipocytes↗
Anatomical basis for impotence following haemorrhoid sclerotherapy.
Impotence has been reported as a rare but important complication of sclerotherapy for haemorrhoids. The relationship between the anterior wall of the rectum and the periprostatic parasympathetic nerves responsible for penile erection was studied to investigate a potential anatomical explanation for this therapeutic complication. A tissue block containing the anal canal, rectum and prostate was removed from each of six male cadaveric subjects. The dimensions of the components of the rectal wall and the distance between the rectal lumen and parasympathetic nerves in the periprostatic plexus were measured in horizontal transverse histological sections of the tissue blocks at the level of the lower prostate gland (i.e. the correct level for sclerosant injection). The correct site of sclerosant in the submucosa was on average 0.6 mm (SD 0.3 mm) deep to the rectal mucosal surface and only 0.7 mm (SD 0.5 mm) in thickness. The nearest parasympathetic ganglion cells were a mean of only 8.1 mm (SD 2.0 mm) deep to the rectal lumen. The close proximity of the rectum to the periprostatic parasympathetic nerves defines an anatomical basis for impotence following sclerotherapy. This emphasises the need for all practitioners to be particularly careful when injecting in this area and for strict supervision of trainees.
Aged↗
Human leukocyte antigens and cancer: is it in our genes?
Human leukocyte antigens (HLAs) are widely expressed cell surface molecules which present antigenic peptides to T-lymphocytes, thus modulating the immune response. The efficiency of peptide presentation by HLAs is dependent on the extreme polymorphism in the HLA-encoding loci within the major histocompatibility complex (MHC). HLA polymorphism is known to alter disease susceptibility and progression in a range of predominantly inflammatory conditions, many of which are T-lymphocyte-mediated. More recently, the importance of alterations in HLA expression and polymorphisms within HLA-encoding loci has emerged in the development of malignancy. This review concentrates on the role of HLA polymorphism in malignant disease, with discussion of the major cancers in which HLA associations have become clear, as well as the potential mechanisms by which HLA polymorphisms may act as important factors, or cofactors, in the pathogenesis of malignant disease. In addition, the role of certain non-HLA genes within the MHC in the pathogenesis of malignancy is also considered briefly.
Cell Transformation, Neoplastic↗
Severe pulmonary toxicity in patients treated with a combination of docetaxel and gemcitabine for metastatic transitional cell carcinoma.
BACKGROUND: Both gemcitabine and docetaxel have been associated with pulmonary toxicity when used as single agents. We report a study in which three of five cases developed pulmonary toxicity (which proved fatal in one case) when these drugs were used in combination to treat metastatic transitional cell cancer. PATIENTS AND METHODS: Three patients developed dyspnoea, in two cases associated with pulmonary infiltrates, whilst receiving the combination of gemcitabine and docetaxel in a phase I trial. The case notes of all five patients entered into this trial were studied. A literature review was undertaken to gain information on reported pulmonary toxicity with the deoxy-cytidine analogues and taxanes given alone or in combination with or without radiotherapy. RESULTS: Three patients developed delayed dyspnoea whilst receiving gemcitabine/docetaxel in combination. This settled with cessation of treatment in one patient, however in the remaining two cases significant hypoxia developed, associated radiologically with evidence of progressive pulmonary infiltrates. One of these patients developed respiratory failure after bronchoscopy and biopsy and died. His chest X-ray changes were consistent with adult respiratory distress syndrome. The transbronchial biopsy and post mortem lung histology in this patient showed diffuse alveolar damage. The remaining patient settled with high dose prednisolone but died subsequently of progressive metastatic disease. CONCLUSION: The combination of gemcitabine and docetaxel showed promising activity in this small study. The development of pulmonary symptoms in three cases with radiological lung infiltrates in two other cases was cause for concern. Patients receiving this drug combination should be closely monitored for similar problems.
Aged↗
Polymerase chain reaction based human leucocyte antigen genotyping for the investigation of suspected gastrointestinal biopsy contamination.
BACKGROUND: Mislabelling or contamination of surgical specimens may lead to diagnostic inaccuracy, particularly within gastrointestinal pathology when multiple small mucosal biopsy specimens are commonly taken, and where a tiny fragment of foreign tissue may be indistinguishable from true biopsy material using histological assessment alone. AIMS: To assess the utility of polymerase chain reaction (PCR) based human leucocyte antigen (HLA) genotyping techniques for the investigation of potentially mislabelled or contaminated gastrointestinal biopsy specimens. PATIENTS: Ten cases (28 samples) in which mislabelling or contamination was suspected, comprising four upper gastrointestinal tract biopsies and six colonoscopic biopsy series. METHODS: Direct and nested PCR-sequence specific primer (SSP) based HLA class II genotyping was performed on DNA extracted from formalin fixed and paraffin wax embedded tissue (23 samples) or peripheral blood leucocytes (five samples). RESULTS: A full HLA-DRB1 genotype was determined in all 28 samples. In seven cases the HLA-DRB1 genotype of the putative contaminant was different to that of the corresponding reference tissue, confirming different individual origins for the contaminant and reference material. In one case the contaminant tissue was shown to possess the same HLA-DRB1 alleles as a second patient (probable source). In the remaining three cases the same HLA-DRB1 alleles were detected within the potential contaminant and reference tissues. CONCLUSIONS: PCR based HLA class II genotyping is a valuable tool for investigating potential contamination or mislabelling within gastrointestinal biopsy specimens and this report has confirmed contamination in seven of ten cases studied.
Adult↗
Calcium oxalate (Weddellite) crystals within ductal carcinoma in situ.
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Breast Neoplasms↗