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Biomedical subjects

P M Speight

Publications and source records attributed to P M Speight.

At least 19 recordsLinked to original sources
PubMed2006

Transfection of CD40 in a human oral squamous cell carcinoma keratinocyte line upregulates immune potency and costimulatory molecules.

BACKGROUND: There is upregulation of class II molecules of the major histocompatibility complex (MHC) by keratinocytes in oral squamous cell carcinoma (OSCC) and inflammatory diseases such as lichen planus. The significance of this expression, or whether it is accompanied by upregulation of membrane-bound costimulatory molecules, is unknown. OBJECTIVES: To compare the expression of CD40, CD80, CD86, MHC class II and intercellular adhesion molecule-1 (ICAM-1), and the ability to induce allogeneic T-lymphocyte proliferation in vitro, of a CD40- OSCC cell line, its CD40+ transfected derivative and null transfectants. METHODS: OSCC cell lines and purified T lymphocytes were cocultured and T cell proliferation recorded. Phenotypes were analysed by flow cytometry. RESULTS: After T lymphocyte proliferation, which all OSCC cell lines were able to induce, there was upregulation of MHC class II and ICAM-1. However, the CD40+ transfectants were the most immunologically potent and were the only cells to show increased expression of CD86 (as well as further upregulation of CD40 and a statistically insignificant rise in CD80). The effects of blocking antibodies on T-cell proliferation were only statistically significant with the CD40+ transfectants. CONCLUSIONS: While not essential, expression of CD40 by OSCC cells is necessary for optimal induction of allogeneic T lymphocytes, possibly because of concurrent upregulation of other membrane-bound costimulatory molecules.

Antigens, CD↗
PubMed2006

Transfection and ligation of CD40 in human oral keratinocytes affect proliferation, adhesion and migration but not apoptosis in vitro.

AIMS: CD40 expression is restricted to Keratinocytes of normal epidermis or stratified squamous epithelium of oral mucosa. Ligation of CD40 inhibits keratinocyte proliferation and apoptosis. The aim of this study was to investigate the functional significance of CD40 in the proliferation, apoptosis, adhesion and migration of human oral keratinocytes in vitro. METHODS: The CD40-negative oral keratinocyte line OSC19, its CD40-positive transfected derivative (OSC19T-CD40) and null transfectants (OSC19T-control), with and without stimulation by soluble protein CD40 ligand (sCD40L) or anti-CD40 antibodies were used. RESULTS: OSC19T-CD40 showed significantly (P < 0.001) slower growth than the null transfectants and parent cells. OSC19T-CD40 proliferation was inhibited by ligation with sCD40L and blocking by two anti-CD40 antibodies, but stimulated by a third. Binding of CD40 with ligand or antibody had no effect on keratinocyte apoptosis in any cell line. The capacity of OSC19T-CD40 cells to adhere to CD40L-coated wells was significantly greater (P < 0.001) than that of parent OSC19 and OSC19T-control cells, and the migration rate of OSC19T-CD40 cells was significantly higher than parent OSC19 (P = 0.038 on fibronectin, P = 0.004 on Matrigel) or OSC19T-control (P =0.017 on fibronectin, P = 0.013 on Matrigel) cells. CONCLUSIONS: CD40 is an important molecule in keratinocyte homeostasis, and has more than one ligand. The ligand that is bound may be critical in oral epithelial homeostasis, the development of malignancy and the behaviour of the subsequent tumour.

Apoptosis↗
PubMed2006

The cost-effectiveness of screening for oral cancer in primary care.

OBJECTIVES: To use a decision-analytic model to determine the incremental costs and outcomes of alternative oral cancer screening programmes conducted in a primary care environment. DESIGN: The cost-effectiveness of oral cancer screening programmes in a number of primary care environments was simulated using a decision analysis model. Primary data on actual resource use and costs were collected by case note review in two hospitals. Additional data needed to inform the model were obtained from published costs, from systematic reviews and by expert opinion using the Trial Roulette approach. The value of future research was determined using expected value of perfect information (EVPI) for the decision to screen and for each of the model inputs. SETTING: Hypothetical screening programmes conducted in a number of primary care settings. Eight strategies were compared: (A) no screen; (B) invitational screen--general medical practice; (C) invitational screen--general dental practice; (D) opportunistic screen--general medical practice; (E) opportunistic screen--general dental practice; (F) opportunistic high-risk screen--general medical practice; (G) opportunistic high-risk screen--general dental practice; and (H) invitational screen--specialist. PARTICIPANTS: A hypothetical population over the age of 40 years was studied. MAIN OUTCOME MEASURES: The main measures were mean lifetime costs and quality-adjusted life-years (QALYs) of each alternative screening scenario and incremental cost-effectiveness ratios (ICERs) to determine the additional costs and benefits of each strategy over another. RESULTS: No screening (strategy A) was always the cheapest option. Strategies B, C, E and H were never cost-effective and were ruled out by dominance or extended dominance. Of the remaining strategies, the ICER for the whole population (age 49-79 years) ranged from pound 15,790 to pound 25,961 per QALY. Modelling a 20% reduction in disease progression always gave the lowest ICERs. Cost-effectiveness acceptability curves showed that there is considerable uncertainty in the optimal decision identified by the ICER, depending on both the maximum amount that the NHS may be prepared to pay and the impact that treatment has on the annual malignancy transformation rate. Overall, however, high-risk opportunistic screening by a general dental or medical practitioner (strategies F and G) may be cost-effective. EVPIs were high for all parameters with population values ranging from pound 8 million to pound 462 million. However, the values were significantly higher in males than females but also varied depending on malignant transformation rate, effects of treatment and willingness to pay. Partial EVPIs showed the highest values for malignant transformation rate, disease progression, self-referral and costs of cancer treatment. CONCLUSIONS: Opportunistic high-risk screening, particularly in general dental practice, may be cost-effective. This screening may more effectively be targeted to younger age groups, particularly 40-60 year olds. However, there is considerable uncertainty in the parameters used in the model, particularly malignant transformation rate, disease progression, patterns of self-referral and costs. Further study is needed on malignant transformation rates of oral potentially malignant lesions and to determine the outcome of treatment of oral potentially malignant lesions. Evidence has been published to suggest that intervention has no greater benefit than 'watch and wait'. Hence a properly planned randomised controlled trial may be justified. Research is also needed into the rates of progression of oral cancer and on referral pathways from primary to secondary care and their effects on delay and stage of presentation.

Aged↗
PubMed2005

Clinico-pathological features of squamous cell carcinoma of the oral cavity in patients <40 years of age.

BACKGROUND: Considerable controversy exists in the literature regarding the clinical course of young patients with oral squamous cell carcinoma (SCC). The purpose of this study was to evaluate the clinico-pathological features of oral SCC among young people. METHODS: From a cohort of 529 patients diagnosed with SCC, 35 (6.6%) were under the age of 40 years. This group was compared to a control group of 110 cases aged over 40 to determine if there were any differences in clinicopathological features between the two groups. RESULTS: In the young group there were 20 males and 15 females. The site was most frequently the tongue (51.3%), followed by the floor of the mouth, the buccal mucosa, and the upper and lower alveolus and gingiva. The local and regional control rate was 64.8% which was similar to that of older patients in this series. CONCLUSIONS: The prognosis of oral SCC in the young patients does not appear to be different from that of the older population. Univariate analysis showed that clinical stage and the mode of invasion were the most significant prognostic factors in both younger and older patients.

Adult↗
PubMed2004

Tumour-derived TGF-beta1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells.

The development of an altered stromal microenvironment is a common feature of many tumours including squamous cell carcinoma (SCC), and there is increasing evidence that these changes in the stroma, which include increased expression of proteases and cytokines, may actually promote tumour progression. A common finding is that stromal fibroblasts become 'activated' myofibroblasts, expressing smooth muscle actin and secreting cytokines, proteases and matrix proteins. We show that myofibroblasts are commonly found in the stroma of oral SCC and are often concentrated at the invasive margin of the tumour. Using oral SCC cells and primary oral fibroblasts, we demonstrate that tumour cells directly induce a myofibroblastic phenotype, and that this transdifferentiation is dependent on SCC-derived TGF-beta1. In turn, myofibroblasts secrete significantly higher levels of hepatocyte growth factor/scatter factor compared with fibroblast controls, and this cytokine promotes SCC invasion through Matrigel, a mixture of basement membrane proteins. This is the first time that this double paracrine mechanism has been demonstrated between squamous carcinoma cells and fibroblasts, and emphasises that cancer invasion can be promoted indirectly by the release of tumour-induced host factors from stroma.

Carcinoma, Squamous Cell↗
PubMed2004

An audit of the efficacy of the oral brush biopsy technique in a specialist Oral Medicine unit.

The diagnosis of oral epithelial dysplasia has traditionally been based upon histopathological evaluation of a full thickness biopsy specimen from lesional tissue. It has recently been proposed that cytological examination of "brush biopsy" samples is a non-invasive method of determining the presence of cellular atypia, and hence the likelihood of oral epithelial dysplasia. The present audit determined, retrospectively the sensitivity, specificity and positive and negative predictive values of the oral brush biopsy technique in the diagnosis of potentially malignant disease in a group of 112 patients attending a specialist Oral Medicine unit. The sensitivity of detection of oral epithelial dysplasia or squamous cell carcinoma of the oral brush biopsy system was 71.4% while the specificity was 32%. The positive predictive value of an abnormal brush biopsy result (positive or atypical) was 44.1%, while the negative predictive value was 60%. It is concluded that not all potentially malignant disease is detected with this non-invasive investigative procedure.

Adult↗
PubMed2004

The histopathology of syphilis of the oral mucosa.

BACKGROUND: Reported cases of syphilis in the United States, Europe and elsewhere are increasing in number. Clinical manifestations are protean, and oral biopsies may be taken where the diagnosis is unsuspected, but data on the histopathology of oral mucosal syphilis are sparse. METHODS: The histopathology of five oral lesions in patients with serologically proven syphilis was reviewed. RESULTS: There were two cases of primary syphilis, one secondary and two tertiary. Epithelial hyperplasia was present in three cases, and was pseudocarcinomatous in one case of primary syphilis, and psoriasiform in the secondary lesion, where heaped-up epithelium surrounded a defined crater covered by flatter epithelium. Plasma cell (primary and secondary disease) and granulomatous (tertiary) infiltrates were prominent. Other features observed were endarteritis (5/5), plasma cell neuritis (3/5) and spirochetes (4/5). CONCLUSIONS: Although no single microscopic feature is specific, a diagnosis of syphilis should be considered where there is unusual epithelial hyperplasia, granulomatous or plasma cell-predominant chronic inflammation, endarteritis and neuritis.

Adult↗
PubMed2003

Opportunistic screening for oral cancer and precancer in general dental practice: results of a demonstration study.

OBJECTIVES: To demonstrate the feasibility of opportunistic oral cancer and precancer screening in general dental practice and to determine the prevalence of relevant lesions and risk habits in a population of general dental practice attenders. DESIGN: A prospective demonstration study, recruiting patients opportunistically. SETTING: General dental practices. METHODS: Eighteen general dental practitioners took part in this study. Each attended training sessions to be advised of the study protocol and the criteria of a positive and negative screen. Patients over the age of 35 years were prospectively and opportunistically recruited. Each patient was asked to complete a health questionnaire concerning age, gender, ethnicity, smoking and drinking habits. The dentist then examined the soft tissues and recorded the presence or absence of lesions independently on a second form. The forms were collated and data were analysed to determine prevalence of lesions and associations with risk habits. RESULTS: Data on 2,265 patients were available for analysis. Oral lesions were detected in 319 patients (14.1%). Ninety-four patients (4.2%) had lesions considered to be either malignant or potentially malignant. There was a significant association between positive lesions and male gender(IRR 1.86, 95% CI 1.22-2.82), heavy smoking (males: IRR 3.68, 95% Cl2.10-6.43: female; IRR 3.58, 954b CI 1.35-9.50) and heavy alcohol use in males (IRR 2.98, 95%q CI 1.06-3.47). CONCLUSIONS: The results suggest that patients attending general dental practices are representative of the general population both in terms of lesion prevalence and high risk habits such as smoking and drinking. This supports the view that opportunistic screening in a general dental practice setting may be a realistic alternative to population screening. Further research is needed to determine the cost effectiveness of this approach and to investigate the value of targeting high risk groups within this population. General dental practice is ideal for the evaluation of such systems prior to extending these studies to other healthcare settings.

Adult↗
PubMed2003

Progress in determining the malignant potential of oral lesions.

The dilemma in managing patients with potentially malignant oral lesions and field change is of deciding which mucosal lesions or areas will progress to carcinoma. Although dysplasia may be predictive, this is not invariable, and there can be considerable inter- and intraexaminer variation in that diagnosis. Recent data on molecular and DNA changes in potentially malignant lesions suggest that it is now feasible to identify those lesions that are truly potentially malignant.

Biomarkers, Tumor↗
PubMed2002

Binding of TGF-beta1 latency-associated peptide (LAP) to alpha(v)beta6 integrin modulates behaviour of squamous carcinoma cells.

The integrin alpha(v)beta6 is not detectable on normal keratinocytes in vivo but expression is increased significantly in oral squamous cell carcinoma where this heterodimer has been shown to play a role in cell migration, invasion and protease expression. Although regarded initially as a fibronectin receptor, alpha(v)beta6 may bind to arginine-glycine-aspartic acid sequences in other matrix molecules including tenascin and vitronectin. Interestingly, alpha(v)beta6 has also been shown to have high affinity for the TGF-beta1 latency associated peptide and to participate in the activation of the TGF-beta1 latent complex. Since TGF-beta1 is present in squamous carcinomas, it is possible that latency associated peptide may modulate malignant keratinocyte behaviour independently from the classical TGF-beta signalling pathways through its interaction with integrins. We show here that when latency associated peptide is immobilised onto a surface, it acts as an alpha(v)beta6-specific ligand for oral squamous carcinoma cells promoting adhesion and haptotactic migration in addition to alpha(v)beta6-dependent increase in pro-MMP-9 expression. In contrast, even very low concentrations of soluble latency associated peptide (0.1 microg ml(-1)) inhibited alpha(v)beta6-dependent adhesion, migration and invasion. Thus alpha(v)beta6-dependent processes of oral squamous cell carcinoma, is likely to be modulated, not only by the local concentration of latency associated peptide in the stroma, but also whether it is immobilised in the matrix or released as a soluble protein.

Antigens, Neoplasm↗
PubMed2002

Meta-analysis of measures of performance reported in oral cancer and precancer screening studies.

OBJECTIVE: To elicit a range of values for sensitivity, specificity and other measures of performance in screening for oral cancer and precancer. METHOD: A literature search which included three databases was conducted. Strict inclusion criteria were applied. Values for sensitivity (Sn) and specificity (Sp), from seven investigations, were expressed as a receiver operator characteristic (ROC) curve. Meta-analysis of the combined results was used to produce a summary operator characteristic (SROC) curve. RESULTS: The pooled weighted value of Sn from the seven studies was 0.796. From the SROC, the corresponding value of Sp at this level of Sn was 0.977 (95% CI 0.941, 0.991). When Sp was held at 0.977, the corresponding value of Sn from the SROC was 0.796 (95% CI 0.594, 0.912). CONCLUSIONS: The reports selected for eventual inclusion revealed a high level of heterogeneity with respect to the location of investigations, prevalence of lesions, the personnel used and other factors. The meta-analysis indicated that overall the studies had high discriminatory ability. The estimates of Sn and Sp, and values obtained for other measures of screening performance, were considered suitable for input to a simulation model in assessing the likely cost-utility of a variety of screening scenarios in further planned research.

False Negative Reactions↗
PubMed2002

Fluorescence biodistribution and photosensitising activity of toluidine blue o on rat buccal mucosa.

The antimicrobial activity of toluidine blue O (TBO) in the presence of red light has been demonstrated for a wide range of microorganisms. The response of tissues to TBO-induced photosensitisation is an important factor in assessing the clinical usefulness of this technique for the treatment of infectious diseases. The aims of this study were to determine the effect of TBO-mediated photosensitisation on rat buccal mucosa and the biodistribution of the photosensitiser in this tissue. An aqueous solution of TBO was applied to one side of the buccal mucosa of the animals. A 6 mm diameter area was then exposed to light (633 nm) from a copper vapour pumped-dye laser. The opposite, untreated, side of the buccal mucosa served as a control. TBO concentrations of 25, 50 and 200 microg/ml, laser light doses of 110, 170 and 340 J/cm(2) were assessed. Control groups of animals were subjected to 340 J/cm(2) laser light alone or to 200 microg/ml TBO alone. Serial sacrifices were performed after 72 h to obtain mucosal tissue samples for histological examination. For the determination of TBO biodistribution, additional groups received the same TBO doses and were sacrificed after 1 min or 10 min. Specimens were removed and frozen immediately for digital fluorescence imaging. No necrotic or inflammatory changes were found in the buccal mucosa of the animals with any of the treatments (using up to 200 microg/ml TBO and 340 J/cm(2) laser light). A high TBO fluorescence in the epithelium, particularly in the keratinised layer, with almost no fluorescence in the underlying connective tissue was demonstrated by the digital imaging. The results of this study suggest that TBO-mediated PDT (within the concentrations and light doses tested) could be a safe antimicrobial approach for the oral infections without damaging the adjacent normal tissue.

Animals↗
PubMed2002

Oral yeast carriage correlates with presence of oral epithelial dysplasia.

Previous studies have suggested a link between the presence of Candida albicans and the development of oral squamous cell carcinoma (OSCC). The aim of the present study was to assess the presence and level of colonisation of oral yeast in patients undergoing an incisional oral mucosal biopsy in order to assess whether the amount of oral yeast present correlated with the presence and degree of oral epithelial dysplastic or neoplastic change. Two hundred and twenty-three patients who were undergoing an incisional biopsy for the diagnosis of an oral mucosal lesion were enrolled in this study. Mouth swills were obtained from each patient for the presence and amount of oral yeast present. Some of the patients (44.6%) had a histopathological diagnosis of either oral epithelial dysplasia (OED) or OSCC and the frequency of oral yeast carriage was significantly greater (P<0.001) in these patients than those without histopathologically detected dysplastic or neoplastic oral lesions. Furthermore, significantly (P<0.001) more patients with OED or OSCC had a higher number of yeast (over 1000 cfu/ml) in their oral cavity than patients without any evidence of epithelial dysplasia or neoplasia histopathologically. The degree of epithelial dysplasia present in these patients also correlated with higher amounts of yeast in the oral cavity (P=0.017). The results of the present study reveal that there is an interaction between oral carriage of yeast and oral epithelial dysplasia, however it remains unclear how yeast infection influences the development and progression of dysplasia.

Adult↗
PubMed2002

Salivary gland tumours.

Salivary gland tumours are a relatively rare and morphologically diverse group of lesions. Although most clinicians and pathologists will have encountered the more common benign neoplasms, few have experience of the full range of salivary cancers, which are best managed in specialist centres. This review considers some current areas of difficulty and controversy in the diagnosis and management of these neoplasms. The classification of these lesions is complex, encompassing nearly 40 different entities, but precise classification and terminology is essential for an accurate diagnosis and for the allocation of tumours to prognostic groups. For many salivary tumours diagnosis is straightforward but the wide range of morphological diversity between and within tumour types means that a diagnosis may not be possible on small incisional biopsies and careful consideration of the clinical and pathological features together is essential. Although tumour grading is important and helpful, it is not an independent prognostic indicator and must be considered in the context of stage. Large malignancies tend to have a poor prognosis regardless of grade and even high-grade neoplasms may do well when they are small. A helpful guide to management of salivary cancers is the '4 cm rule'.

Adenocarcinoma↗
PubMed2002

Labial tuberculosis: a unique cause of lip swelling complicating HIV infection.

BACKGROUND: HIV disease has many oral manifestations including tuberculosis, which most commonly presents as irregular ulceration of the tongue or the palate. We detail an HIV-infected patient found to have tuberculosis of the lip. CONCLUSIONS: To our knowledge tuberculosis of the lips has never been reported in conjunction with HIV infection, and in this case establishing the oral diagnosis resulted in the diagnosis of disseminated disease.

AIDS-Related Opportunistic Infections↗
PubMed2002

A clinicopathologic and immunohistochemical analysis of melanotic neuroectodermal tumor of infancy.

OBJECTIVE: The purpose of this study was to review the features of 8 cases of melanotic neuroectodermal tumor of infancy (MNTI) of the jaws with respect to the expression of NB84, CD99, PGP 9.5, specific cytokeratins, and Ki-67, markers not previously reported in this entity. STUDY DESIGN: A clinicopathologic and immunohistochemical analysis of MNTIs in 8 children was undertaken. RESULTS: Patients were aged 2(1/2) months to 14 months. Seven were males. Seven lesions affected the maxilla. Microscopically, collections of larger, melanocyte-like cells were admixed with smaller, neuroblast-like cells. All MNTIs contained melanin; although most showed cellular atypia, mitoses were infrequent (<2 per 10 high-power fields). However, in one lesion in which the melanocyte-like cells appeared less differentiated, 7 mitoses per 10 high-power fields were counted. The larger cells expressed cytokeratins 7 (4/8), 8 (8/8), 18 (6/8), and 19 (3/8); PGP 9.5; neuron-specific enolase (6/8); S100; HMB45; and chromogranin A (2/8). The small cells expressed CD56 (7/8), neuron-specific enolase (7/8), synaptophysin (3/8), PGP 9.5 (3/8), and chromogranin A (2/8). No MNTIs expressed NB84. The most mitotically active tumor was the only one to show membrane expression of CD99 (by both cell populations), have a detectable Ki-67-positive fraction (25% in both the large- and small-cell components), behave aggressively, and require bilateral maxillectomy. All other MNTIs responded to local excision, and none metastasized. CONCLUSIONS: Most MNTIs are benign and respond to conservative excision. Histology is an unreliable means of predicting clinical behavior, but this study has identified some morphologic and phenotypic features that may indicate a more aggressive lesion.

12E7 Antigen↗
PubMed2001

AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9.

The integrin alphaVbeta6 is a fibronectin receptor, which is not detectable on normal epithelium but is neo-expressed in oral epithelial dysplasia and oral squamous-cell carcinoma (SCC), suggesting a role in promoting malignant behaviour and tumour progression. We used transfection and retroviral infection to create a panel of SCC cell lines expressing various levels of alphaVbeta6 to examine this possibility. We found that increased expression of alphaVbeta6 in malignant keratinocytes up-regulates MMP-9 and MMP-2 expression and promotes invasion in an MMP-9-dependent manner. Our results suggest a possible mechanism for the involvement of alphaVbeta6 in squamous carcinoma in vivo.

Animals↗