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S Pateromichelakis

Publications and source records attributed to S Pateromichelakis.

At least 19 recordsLinked to original sources
PubMed2001

Profiling clonality and progression in multiple premalignant and malignant oral lesions identifies a subgroup of cases with a distinct presentation of squamous cell carcinoma.

A cohort of head and neck cancer patients, without exposure to tobacco and alcohol, presented with multiple preneoplastic and neoplastic lesions, the natural history of which may span several decades. Examination of these cases provides an opportunity to study the relationship between genetic, morphological, and clonal progression in these fields and establish whether they represent a unique presentation of squamous cell carcinoma. The presence of a common novel microsatellite allele, a common breakpoint or concordant allelic imbalance at multiple loci, reveals that a high proportion of these serial lesions arise due to spread of a precursor. The tumors arising in these patients were typically nonaggressive, although metastases developed at a late stage, supporting the notion that the genotype results in a phenotype with a propensity for lateral spread, rather than invasion. Different genetic aberrations were detected in morphologically similar phenotypes such that no consistent early or late events were associated with development of premalignant lesions. Combining information about the clinicopathological features and histological examination of the margins with that derived from clonality analysis reveals that a subgroup of patients, without exposure to the traditional risk factors associated with this disease, developed multiple clonally related oral lesions and represents a unique presentation of head and neck squamous cell carcinoma. We suggest the term clonal cancerization to describe multiple premalignant and malignant lesions when there is conclusive evidence that they arise due to lateral spread from a common precursor.

Adult↗
PubMed2000

A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization.

Distinguishing true precursor lesions on the basis of clinical or histological features alone is unreliable but is important so that appropriate intervention can be instigated. Preliminary studies have shown that a microsatellite assay may provide important new prognostic information. To build on these observations, we have performed a case-control study to establish whether we can be confident about incorporating this new information into clinical practice. We have determined the frequency of allelic imbalance (AI) within key chromosomal regions, by matching 39 cases with dysplastic oral lesions that developed a tumor on the same side of the mouth, for as many variables as possible, with controls presenting with similar lesions that did not progress to malignancy when followed for the same period. Our findings confirm that the group that developed tumor had precursor lesions that harbor AI at more loci (P = 0.002). However, no consistent patterns of AI were associated with the three grades of dysplasia: mild, moderate, and severe. One-third of the tumors developed at the same site as the dysplastic lesion and two-thirds at a different site, which revealed that the presence of these aberrations in a dysplastic lesion provided information about the risk of malignant change within a larger field. This suggests that the process of field cancerization is more widespread than previously recognized. On the basis of these findings, we advocate complete excision of all suspicious areas that show AI at two or more key loci, regardless of the degree of dysplasia. However, because the remaining mucosa is also "at risk," these cases should also be targeted to receive dietary advice and chemoprevention, to minimize their risk of tumor formation at a distant site.

Adult↗
PubMed2000

The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon.

The FHIT (fragile histidine triad) gene at chromosome 3p14.2 spans the FRA3B fragile site and encodes for a diadenosine triphosphate hydrolase-type protein. FHIT is frequently abnormal in solid tumours including those of the upper aerodigestive tract (UAT) and has therefore been proposed as a tumour-suppressor gene. This proposition was evaluated here for oral squamous cell carcinoma (SCC) using microsatellite analysis, reverse transcription-polymerase chain reaction (RT-PCR), FHIT exon 5 PCR and direct sequencing. Fifty-eight primary oral SCCs were examined with two FHIT gene microsatellite markers (D3S4103 and D3S1300) and two markers flanking FHIT. Allelic imbalance (AI) occurred in 28 of 52 informative cases (54%) at one or both FHIT markers (D3S4103: 53%; D3S1300: 42%). A significant association was noted between frequency of AI and advanced stage tumours for D3S4103 but not between AI frequency and smoking. AI frequency at D3S1300 and at a flanking marker correlated with low survival. Of eight oral/UAT SCC cell lines examined, six produced abundant wild-type transcript and one yielded mostly truncated transcripts, the most abundant of which lacked exons 5-7. A double deletion was also detected in one of 11 primary oral SCCs. Our microsatellite assay results show that the FHIT gene is frequently disrupted in oral SCC. However, as FHIT was shown to be expressed normally in the great majority of oral/UAT SCCs studied, its likely involvement in the molecular pathogenesis of the disease as a tumour suppressor remains doubtful.

Acid Anhydride Hydrolases↗
PubMed2000

Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment.

Improvements in surgery and radiotherapy techniques have led to only a modest increase in the 5-year survival rate for patients with head and neck cancer. This is because the pattern of clinical disease is changing, such that locoregional recurrence now accounts for fewer treatment failures, but more patients develop a second primary cancer or distant metastatic disease. In this study, we have used the p53 phage plaque assay, immunocytochemistry, and mutational analysis to assess the contribution of minimal residual cancer and genetic aberrations in clinically normal upper aerodigestive tract mucosa to treatment failure. Eighteen consecutive patients with oral tumors, with conventional clear margins, have been followed for a minimum of 36 months. Molecular assessment identified tumor-positive surgical margins for 6 of 11 assessable patients and additional tumor-positive lymph nodes for three cases. Disseminated malignant cells were detected in the hematopoietic cell compartment for six cases, and one patient had molecular evidence of field cancerization. Locoregional recurrence developed in five patients with tumors harboring a p53 gene mutation; four of these were associated with tumor-positive surgical margins, and one was associated with molecular evidence of field cancerization. Radiotherapy to the primary site did not prevent development of local recurrence when the residual tumor harbored a p53 gene mutation. Three of six cases with a tumor-positive bone marrow aspirate developed distant metastases. These findings reveal that molecular and immunocytochemical detection of minimal residual cancer and field cancerization can help identify patients who may develop locoregional or distant recurrence and justify further studies to evaluate the contribution of these remaining malignant cells to treatment failure.

Adult↗
PubMed1999

Location of candidate tumour suppressor gene loci at chromosomes 3p, 8p and 9p for oral squamous cell carcinomas.

To help define the location of tumour suppressor genes implicated in the pathogenesis of oral squamous cell carcinoma (SCC), we have used microsatellite assay and restriction fragment length polymorphism (RFLP) analysis to screen 48 primary SCC for allelic imbalance (AI) with 32 polymorphic markers at chromosome 3p, and prepared a detailed deletion map. The finding of a high frequency of AI at specific regions, together with the presence of multiple small interstitial deletions involving these loci, identifies 5 areas at this chromosome arm that may harbour tumour suppressor genes. No sequence aberrations affecting the von Hippel Lindau (VHL) and fragile histidine triad (FHIT) genes, which reside within the candidate tumour suppressor gene areas at this chromosome arm, were identified. A more limited analysis of polymorphic sequences at 8p and 9p supports the existence of at least 2 areas that harbour tumour suppressor genes at 8p and evidence that additional targets for deletion reside centromeric and telomeric to the p16 gene at 9p21.

Acid Anhydride Hydrolases↗
PubMed1999

Patient-specific mutation databases for oral cancer.

Development of databases, summarising the genetic events associated with oral squamous cell carcinoma (SCC), should increase our understanding of the molecular basis of these lesions. Additionally, databases will help establish whether different cancer subtypes show different growth characteristics, because the multistage carcinogenic process is different in the various tumour subtypes. This new knowledge may also provide new prognostic information, as these aberrations represent fundamental biological characteristics of each tumour. To assess the value of incorporating the results from loss of heterozygosity (LOH) analysis into patient-specific mutation databases, we have carried out microsatellite analysis with 52 polymorphic markers at 13 key chromosomal regions implicated in the pathogenesis of head and neck cancers. Altered expression of the Rb, p53 and DCC tumour suppressor genes has also been studied by immunohistology. Our results shed light on the different pathways that lead to cancer and reveal that a variety of different patterns of allelic imbalance (AI) were detected at all TNM stages, reflecting the different clinical behaviour that tumours classified as being of the same TNM stage may exhibit. Summarising the level of genetic damage as a fractional allelic loss (FAL) score and the presence of AI at 3p22-26, 3p14.3-12.1 and 9p21 was found to be a better predictor of outcome than the TNM system. This finding suggests that molecular data can be incorporated into conventional staging systems to provide more accurate prognostic information for this group of patients.

Adult↗
PubMed1999

New insights into p53 protein stabilisation in oral squamous cell carcinoma.

p53 is a transcription factor which regulates cell proliferation and apoptosis to prevent division of potentially malignant cells. In many tumours mutation of the p53 gene leads to stabilisation of this protein which can be detected by immunohistochemistry (IHC). However, there are many reports describing detection of p53 by IHC in the absence of gene mutation, and in these cases other factors stabilise p53. To shed light on the mechanisms which permit detection of this protein in these mutation-negative cases we have examined 45 primary oral squamous cell carcinomas (SCCs) by IHC and gene sequencing for p53 (exons 4-8) and related the results to a FAL score (determined using microsatellite assay and expressing the number of loci showing allelic imbalance as a fraction of the total number of informative markers for each case). We also investigated the pattern of MDM2 expression in these tumours. High levels of p53 protein were detected in 24/45 cases and point mutations involving exons 4-9 were seen in 11 cases. A further four cases harboured deletions or a stop codon. For 6/48 cases there was concordance of AI within the p53 gene and mutation. However nine cases showed p53 mutation only and 5 AI without mutation, suggesting that oral tumours frequently retain one normal p53 allele. Detection of p53 by IHC correlated strongly with the FAL score. Thus whilst it is possible that some tumours harbour p53 mutations outside the open reading frames examined, or are missed due to sequencing a mixture of normal and tumour tissue, a subgroup of tumours may express high levels of wild-type p53 as a reflection of the high FAL score and ongoing genomic stress. Levels of MDM2 transcripts and protein were similar in all SCCs examined. However, MDM2 may be non-functional, or there may be defects affecting other important regulatory proteins in tumours which which express wild type p53 protein.

Adult↗
PubMed1999

The prognostic significance of allelic imbalance at key chromosomal loci in oral cancer.

Forty-eight primary oral squamous cell carcinomas (SCC) were screened for allelic imbalance (AI) at 3p24-26, 3p21, 3p13, 8p21-23, 9p21, 9q22 and within the Rb, p53 and DCC tumour suppressor genes. AI was detected at all TNM stages with stage 4 tumours showing significantly more aberrations than stage 1-3. A factional allelic loss (FAL) score was calculated for all tumours and a high score was associated with development of local recurrence (P = 0.033) and reduced survival (P = 0.0006). AI at one or more loci within the 3p24-26, 3p21, 3p13 and 9p21 regions or within the THRB and DCC genes was associated with reduced survival. The hazard ratios for survival analysis revealed that patients with AI at 3p24-26, 3p13 and 9p21 have an approximately 25 times increase in their mortality rate relative to a patient retaining heterozygosity at these loci. AI at specific pairs of loci, D3S686 and D9S171 and involving at least two of D3S1296, DCC and D9S43, was a better predictor of prognosis than the FAL score or TNM stage. These data suggest that it will be possible to develop a molecular staging system which will be a better predict of outcome than conventional clinicopathological features as the molecular events represent fundamental biological characteristics of each tumour.

Adult↗
PubMed1998

Allelic imbalance at chromosomal loci implicated in the pathogenesis of oral precancer, cumulative loss and its relationship with progression to cancer.

A microsatellite assay was used to screen 31 potentially malignant oral lesions presenting as leukoplakia and erythroplakia, with histological evidence of dysplasia, for genetic abnormalities at loci which frequently show allelic imbalance when oral squamous cell carcinomas (SCC) are examined. The microsatellite and restriction fragment length polymorphism (RFLP) markers selected were at 3p21, 8p21-23, 9p21 and included sequences within the Rb (13q14.2), p53 (17p13.1) and DCC (18q21.1) tumour suppressor genes. 8 patients subsequently developed an invasive tumour at the same site, or within 2 cm of the premalignant lesion. A further 8 patients developed SCC at a distant site. Seventy-seven per cent (24/31) of these potentially malignant lesions showed allelic imbalance (AI) and 55% (17/31) of cases showed microsatellite instability (msi). The probability of developing SCC was much greater for patients with lesions showing AI at two or more relevant loci (P = 0.008 by the logrank test) than the group with AI at fewer loci. The estimated probability of development of SCC in this group by 5 years was 73% (95% Cl: 50-92%). This suggests that determining the number of genetic abnormalities in a potentially malignant lesion can help identify patients with true precancers who should be followed closely to ensure that they receive chemoprevention and appropriate advice to limit risk factors, and to allow the early detection of invasive lesions.

Adult↗
PubMed1997

Field cancerisation of the oral cavity: comparison of the spectrum of molecular alterations in cases presenting with both dysplastic and malignant lesions.

Dysplastic lesions and invasive oral squamous cell carcinoma (SCC) from patients with field change were screened by restriction fragment length polymorphism (RFLP) and microsatellite assay. All tumours contained more genetic changes than the matched dysplasia which are likely to represent progression. Four of the 15 dysplastic lesions harboured the same abnormalities detected in the tumour and some paired lesions showed identical novel microsatellite alleles. The finding of identical 'genetic fingerprints' in dysplastic lesions and invasive carcinoma from the same patient provides strong evidence that these dysplasias are precursor lesions and that multiple lesions have probably arisen due to transfer of the progeny of an altered cell. Eight of the 15 dysplastic lesions showed alterations which were not present in the matched cancer, showing that evolution of subclones, or fusion of multiple clones also occurs. A further case showed loss of different alleles in the paired samples. These findings highlight the complexity of the genetic abnormalities present in the mucosa of patients with field change and suggests that the origin of these altered foci may be diverse.

Adult↗
PubMed1995

Cardiorespiratory effects of intravascular injections of lidocaine in the anesthetized rat. Comparisons between arterial and venous routes of administration.

The consequences of two types of intravascular injections of lidocaine 1.5 to 15 mg/kg on three cardiorespiratory parameters were studied in 16 anesthetized rats. Administration of the local anesthetic via either the internal carotid artery (n = 8) or the external jugular vein (n = 8) caused hypotension, bradycardia, and respiratory slowdown. Hypotension was significantly greater after external jugular injections; these were also associated with larger reductions in heart rate. Respiratory attenuation was generally similar for both routes, but high lidocaine doses (9 mg/kg) given via the external jugular were briefly the cause of significantly more respiratory depression. When given via the external jugular, lidocaine 15 mg/kg proved lethal in seven of nine instances. There were no lethal consequences when the same dose was administered via the internal carotid artery. These results offer no evidence in support of claims that the accidental retrograde flow of clinical doses of local anesthetics to the brain via the internal carotid artery can be the cause of hitherto unsuspected high levels of toxicity, leading to respiratory depression and even death.

Animals↗
PubMed1992

Circulatory and respiratory effects of lidocaine administered into the rat maxillofacial circulation.

The inadvertent intra-arterial administration of local anesthetics is a serious hazard of oral operations. For this reason, the circulatory and respiratory consequences of introducing lidocaine into the maxillofacial (MF) arterial circulation were examined in anesthetized rats. Lidocaine boluses of 0.3 to 6.0 mg/kg increased infusion pressure (IP) by up to 85%, signifying considerable local vasoconstriction; following a 6.0 mg/kg injection, heart rate (HR) remained unaffected, mean blood pressure (BP) increased by 5%, and respiratory rate (RR) decreased by 20%. Infusions of 50 or 150 micrograms/kg/min for 30 minutes had no effect on the preceding parameters, but within 15 minutes of infusing lidocaine at 600 micrograms/kg/min, IP increased by 97% and RR decreased by 31%; BP and HR remained unaffected. It was concluded that the main consequences of administering plain lidocaine at the aforementioned doses into the rat MF arterial bed were considerable local vasoconstriction and a large reduction in respiratory rate. Heart rate remained unaffected by lidocaine; neither it nor blood pressure is a reliable indicator of approaching systemic toxicity.

Anesthesia, Dental↗
PubMed1991

Effects of mepivacaine, prilocaine and lidocaine on the induced constriction of the maxillofacial vasculature of the rat.

Infusions of mepivacaine 5 or 50 micrograms.min-1 and prilocaine 50 micrograms.min-1 for 10 min into the maxillofacial arterial vasculature of the anaesthetized rat curtailed significantly rises in infusion pressure induced by the administration of adrenaline via the same route. The effect of mepivacaine was significantly greater than that of prilocaine. Such anti-constrictory action following intraluminal infusion, also shown by lidocaine in a previous study, contrasts with the variable (dilatory or constrictory) consequences of perivascular injections of the same local anaesthetics. Moreover, the equi-constrictory effects of (a) 1.10(-3) IU felypressin and (b) 120 ng adrenaline were attenuated to the same extent by lidocaine 5 micrograms.min-1 for 10 min, demonstrating that the anti-constrictory action of local anaesthetics is not specifically anti-adrenergic as has been suggested previously.

Animals↗
PubMed1988

Local anaesthesia efficacy: discrepancies between in vitro and in vivo studies.

Electrophysiological studies on isolated nerves have been used extensively in the past to assess the comparative efficiency of local anaesthetics as agents of peripheral nerve blockade. It is shown here that three closely related amide local anaesthetics behave differently in vitro and in vivo. In terms of onset of action and of maximum suppression of the evoked action potential, mepivacaine proved a less efficient anaesthetic than lidocaine or prilocaine on isolated nerves, but in parallel studies on the sciatic nerve of live animals and in the absence of vasoconstrictors: (a) mepivacaine's potency was superior to that of the other two agents, (b) its speed of onset of anaesthetic action was at least as good and (c) its duration of action was found to be considerably longer. These results, in combination with the physical properties of the anaesthetics examined, favour differential ionization as the cause of the reduced performance of mepivacaine in the nerve bath. Thus, studies on isolated nerves, which are often quoted in the pharmacological literature, can be poor guides to the in vivo comparative efficacy of local anaesthetics.

Anesthetics, Local↗
PubMed1986

Effects of i.a. lignocaine on adrenaline-induced vasoconstriction.

The effects of i.a. administered lignocaine on the in vivo response of the vascular bed supplied by the lingual, external maxillary and posterior auricular branches of the common carotid artery were studied in the rat. Infusions of lignocaine in concentrations of 10-1000 micrograms ml-1 administered at the rate of 0.05 ml min-1 for 10 min did not affect vascular resistance or arterial pressure in the common carotid artery. However, following such infusions, the increase of vascular resistance caused by bolus doses of adrenaline (20-120 ng in 0.1 ml) was inhibited, indicating lignocaine-adrenaline antagonism. Responses to adrenaline remained significantly depressed 60 min after the termination of a 100-micrograms ml-1 or higher lignocaine infusion.

Animals↗
PubMed1986

The effects of ornipressin and adrenaline on lignocaine nerve blocks.

An electrophysiological method measuring nerve conduction following the electrical stimulation of a sciatic nerve branch in anaesthetised rats was used to evaluate under strictly controlled conditions the effects of 1:100,000 adrenaline and of 0.03 IU X ml-1 ornipressin on the speed of onset, depth and duration of lignocaine anaesthesia. It was shown that compared with plain lignocaine, lignocaine with ornipressin produced shorter onset of anaesthesia and improved its depth and duration. Adding adrenaline to lignocaine merely extended its duration of action. Ornipressin, therefore, even at low concentration, can be considered as a viable alternative vasoconstrictor to adrenaline, the use of which is undesirable in some categories of patients.

Action Potentials↗
PubMed1982

Prostaglandin E1-induced sensitization of A delta moderate pressure mechanoreceptors.

Prostaglandins of the E series (PGEs) have been detected in high quantities in inflamed tissues; when injected in the circulation that supplies the skin they cause inflammation and pain. Evidence of PGE sensitization of C-nociceptors (polymodals) already exists. The present work establishes that PGE1 has a wider sensitizing effect: when injected subdermally it affects mechanoreceptive elements as well. Of moderate-threshold, slow-adapting A delta mechanoreceptors isolated in the skin of the rat leg and responding to punctate stimulation, 79% were sensitized by PGE1 injections nearby (8--12 mm) as judged by their increased responses to innocuous stimulation (0.5--5 g delivered by a stylus with 0.5 mm tip diameter). Of such units, 10.5% were not sensitized and another 10.5% were inhibited or lost. Controls showed at most a small and transient increase immediately following the injection whereas the PGE1 effect lasted from between 30 min to 3 h or longer. These results are discussed in connection with mechanoreceptor sensitization by other pain-producing and irritant substances. At the receptor level, 'nociception' under abnormal conditions (e.g. inflammation) may not be solely mediated by unambiguously 'nociceptive' units; in such conditions a wider sensitization of receptive elements may be a contributing factor in hyperalgesic or hyperaesthetic phenomena.

Alprostadil↗