The nanometre limits of ballistic and diffusive hot-hole mediated nonlocal molecular manipulation.

We report an experimental investigation into the surface-specific and experimental limits of the range of STM induced nonlocal molecular manipulation. We measure the spot-size of the nonlocal manipulation of bromobenzene molecules on the Si(111)-7 × 7 surface at room temperature at two voltages and for a wide range of charge-injection times (number of hot charge-carriers) from 1 s up to 500 s. The results conform to an initially ballistic, 6-10 nm, and then hot-hole diffusive, 10-30 nm, transport away from the localised injection site. This work gives further confirmation that nonlocal molecular manipulation by STM directly reveals the ultrafast transport properties of hot-charge carriers at surfaces.

Intracranial spread of IgG4-related disease via skull base foramina.

IgG4-related disease (IgG4-RD) is a newly recognised, multiorgan, inflammatory disease, and its full clinical spectrum remains undefined. We present a biopsy-proven case of IgG4-RD presenting with a parapharyngeal mass with intracranial extension and possible involvement of the brain parenchyma. We highlight the importance of considering the diagnosis in those presenting with tumefactive lesions, leptomeningitis or pachymeningitis and emphasise the value of securing a tissue diagnosis so that appropriate long-term treatment can be instigated and complications avoided.

Validation of a novel diagnostic standard in HPV-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV) testing in oropharyngeal squamous cell carcinoma (OPSCC) is now advocated. Demonstration of transcriptionally active high-risk HPV (HR-HPV) in fresh tumour tissue is considered to be the analytical 'gold standard'. Clinical testing has focused on formalin-fixed paraffin-embedded (FFPE) tissue at the expense of sensitivity and specificity. Recently, a novel RNA in situ hybridisation test (RNAscope) has been developed for the detection of HR-HPV in FFPE tissue; however, validation against the 'gold standard' has not been reported. METHODS: A tissue microarray comprising FFPE cores from 79 OPSCC was tested using HR-HPV RNAscope. Analytical accuracy and prognostic capacity were established by comparison with the reference test; qRT-PCR for HR-HPV on matched fresh-frozen samples. RESULTS: High-risk HPV RNAscope had a sensitivity and specificity of 97 and 93%, respectively, against the reference test. Kaplan-Meier estimates of disease-specific survival (DSS, P=0.001) and overall survival (OS, P<0.001) by RNAscope were similar to the reference test (DSS, P=0.003, OS, P<0.001) and at least, not inferior to p16 immunohistochemistry +/- HR-HPV DNA-based tests. CONCLUSION: HR-HPV RNAscope demonstrates excellent analytical and prognostic performance against the 'gold standard'. These data suggest that the test could be developed to provide the 'clinical standard' for assigning a diagnosis of HPV-related OPSCC.

Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study.

BACKGROUND: The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. METHODS: A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. RESULTS: There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). CONCLUSIONS: A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers.

Site- and energy-selective intramolecular manipulation of polychlorinated biphenyl (PCB) molecules.

We demonstrate the conversion of an adsorbed precursor state of polychlorinated biphenyl (PCB) molecules on the Si(111)-7 × 7 surface at room temperature into a more stable configuration via site- and energy-selective atomic manipulation in the scanning tunneling microscope (STM). Whereas molecular desorption is maximized by electron injection into the chemisorbed molecular ring at low voltage, injection into the physisorbed molecular ring above a threshold voltage (2.5 V) favors the reconfiguration of the bonding. The results clearly demonstrate both intramolecular charge localization and intramolecular charge transportation as key ingredients in the atomic manipulation of individual polyatomic molecules.

Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations occur in head and neck squamous cell carcinoma (HNSCC) and are most frequently detected in the displacement-loop (D-loop) region. The D-loop is considered to be important because it controls mitochondrial gene expression and mtDNA replication. There is currently no evidence that mtDNA mutations can be used as prognostic or predictive biomarkers in HNSCC. METHODS: We used denaturing high performance liquid chromatography to screen the entire mitochondrial genome of six oral squamous cell carcinoma-derived cell lines and then focused on detecting D-loop abnormalities in 34 HNSCC tissue samples. RESULTS: Mitochondrial DNA mutations are not ubiquitous in HNSCC because only half of the cell lines had detectable mtDNA abnormalities following screening of the entire mitochondrial genome and only 18% (6 of 34) of tissue samples had D-loop mutations. There was no correlation between D-loop mutations and determinates of clinical outcome; specifically, tumour stage and the expression of hypoxia-inducible genes included in a highly prognostic hypoxia metagene. CONCLUSIONS: Taken together, these data suggest that mtDNA D-loop mutations are stochastic events that may not significantly influence the biology of HNSCC and supports the hypothesis that mtDNA mutations in cancer represent bystander genotoxic damage as a consequence of tumour development and progression.

Two-electron dissociation of single molecules by atomic manipulation at room temperature.

Using the tip of a scanning tunnelling microscope (STM) to mechanically manipulate individual atoms and molecules on a surface is now a well established procedure. Similarly, selective vibrational excitation of adsorbed molecules with an STM tip to induce motion or dissociation has been widely demonstrated. Such experiments are usually performed on weakly bound atoms that need to be stabilized by operating at cryogenic temperatures. Analogous experiments at room temperature are more difficult, because they require relatively strongly bound species that are not perturbed by random thermal fluctuations. But manipulation can still be achieved through electronic excitation of the atom or molecule by the electron current tunnelling between STM tip and surface at relatively high bias voltages, typically 1-5 V. Here we use this approach to selectively dissociate chlorine atoms from individual oriented chlorobenzene molecules adsorbed on a Si(111)-7 x 7 surface. We map out the final destination of the chlorine daughter atoms, finding that their radial and angular distributions depend on the tunnelling current and hence excitation rate. In our system, one tunnelling electron has nominally sufficient energy to induce dissociation, yet the process requires two electrons. We explain these observations by a two-electron mechanism that couples vibrational excitation and dissociative electron attachment steps.

Malignant transformation of calcifying epithelial odontogenic tumour with solitary pulmonary metastasis.

This report describes the management of a case of calcifying epithelial odontogenic tumour (CEOT) that underwent malignant transformation and metastasized to the lung. The solitary pulmonary metastasis was discovered incidentally on computed tomography (CT) imaging of the neck. It appears that only one previous case with proven pulmonary metastasis has been reported in the literature, which involved multiple pulmonary deposits managed with platinum chemotherapy. The long-term prognosis of metastatic CEOT is therefore unknown. In the case presented here, the patient was managed successfully with surgery alone. There is often diagnostic uncertainty because histological features of benign, recurrent, and malignant CEOT are not dissimilar. Ki-67 immunohistochemistry is helpful, as higher levels are more indicative of malignancy. We consider that in cases of suspected recurrent and malignant CEOT, CT imaging of the thorax and abdomen as part of follow-up may identify metastases early, resulting in earlier treatment, an improved prognosis, and reduced morbidity and mortality.

Healing of tooth extraction sockets in the streptozotocin diabetic rat model: Induction of cartilage by BMP-6.

Cartilage does not form in the tooth extraction socket of the normal rat. The aim of the study was to determine if adding BMP-6 to the extraction socket would cause chondrogenic differentiation in the diabetic rat. A group of 8-week-old rats were injected intraperitoneally with a diabetogenic agent, streptozotocin, and a control group received citrate buffer only. Three weeks later, the maxillary molar teeth were extracted and either BMP-6 or saline applied to the extraction sockets. Rats from each group were killed on days 3, 5, 7, and 9 after tooth extraction. In the diabetic rats treated with BMP-6, there was a cellular subperiosteal reaction at day 3 in the extra-alveolar tissues, which by day 7 had formed a large mass of cartilage. Cartilage was induced in the subperiosteal region of the socket extra-alveolar bone following the application of BMP-6 in the diabetic rat.

Nonlocal desorption of chlorobenzene molecules from the Si(111)-(7×7) surface by charge injection from the tip of a scanning tunneling microscope: remote control of atomic manipulation.

We report the nonlocal desorption of chlorobenzene molecules from the Si(111)-(7×7) surface by charge injection from the laterally distant tip of a scanning tunneling microscope and demonstrate remote control of the manipulation process by precise selection of the atomic site for injection. Nonlocal desorption decays exponentially as a function of radial distance (decay length ∼100 A) from the injection site. Electron injection at corner-hole and faulted middle adatoms sites couples preferentially to the desorption of distant adsorbate molecules. Molecules on the faulted half of the unit cell desorb with higher probability than those on the unfaulted half.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

Regulating the femtosecond excited-state lifetime of a single molecule.

The key to controlling reactions of molecules induced with the current of a scanning tunneling microscope (STM) tip is the ultrashort intermediate excited ionic state. The initial condition of the excited state is set by the energy and position of the injected current; thereafter, its dynamics determines the reaction outcome. We show that a STM can directly and controllably influence the excited-state dynamics. For the STM-induced desorption of toluene molecules from the Si(111)-7x7 surface, as the tip approaches the molecule, the probability of manipulation drops by two orders of magnitude. A two-channel quenching of the excited state is proposed, consisting of an invariant surface channel and a tip height-dependent channel. We conclude that picometer tip proximity regulates the lifetime of the excited state from 10 femtoseconds to less than 0.1 femtoseconds.

Clinicopathological features of squamous cell carcinoma of the oral cavity and oropharynx in young patients.

Our aim was to examine the clinicopathological features of squamous cell carcinoma (SCC) of the oral cavity and oropharynx in a group of young patients who were dignosed during a 15-year period (2000-2014). Patients' clinical details, risk factors, and survival were obtained from medical records. Formalin-fixed, paraffin-embedded, tissue was tested for high-risk human papillomavirus (HPV). The results were compared with those of a matching group of older patients. We identified 91 patients who were younger than 45 years old, and the 50 youngest patients were studied in detail. The male:female ratio was 2:1, with more tumours located in the oral cavity than in the oropharynx (35 compared with 15). HPV-related SCC was restricted to the oropharynx. When matched for site, stage and HPV status, five-year overall survival was similar in young and matched older patients (log-rank test, p=0.515). Our findings suggest that young patients with oral SCC have a disease profile similar to that of older patients with the condition. It is plausible that prognostic information generally available for oral cancers is applicable to young patients with the disease.

Interventions for the treatment of oral and oropharyngeal cancers: surgical treatment.

BACKGROUND: Oral and oropharyngeal cancers can be managed by surgery alone or with any combination of radiotherapy, chemotherapy and immunotherapy/biotherapy. Opinions on the surgical treatment, the optimal combinational therapy and the sequence of treatments in combinational therapy varies enormously. OBJECTIVES: To determine which surgical treatment modalities for oral and oropharyngeal cancers lead to the best outcomes compared with other surgical, radiotherapy, chemotherapy or immunotherapy/biotherapy combinations. SEARCH STRATEGY: Electronic search of the Cochrane Oral Health Group Trials Register, CENTRAL, MEDLINE, OLDMEDLINE, EMBASE, AMED and the National Cancer Trials Database. Reference lists from relevant articles were searched and the authors of eligible trials were contacted. Date of the most recent searches: July 2007. SELECTION CRITERIA: Randomised controlled trials of surgery alone or in combination with chemotherapy, radiotherapy or immunotherapy/biotherapy for the treatment of primary oral or oropharyngeal cancer or both. DATA COLLECTION AND ANALYSIS: A minimum of two review authors conducted data extraction. Risk ratios were calculated for dichotomous outcomes at different time intervals, and hazard ratios were extracted or calculated for disease-free survival, total mortality, and disease-related mortality. Additional information from trial authors was sought. Data on adverse events were collected from the trial reports. MAIN RESULTS: Thirty-one trials satisfied the inclusion criteria, only 13 of which were assessed as low risk of bias. Trials were grouped into 12 main comparisons. There were no trials that compared different surgical modalities of the primary tumour itself. However, there were a number of trials comparing different approaches to managing the cervical lymph nodes. The majority of treatment regimens under evaluation were surgery in combination with other modalities. As individual treatment regimens within each comparison varied, meta-analysis was inappropriate in most instances. Only two trials could be pooled, comparing concomitant radio/chemotherapy (with surgery) versus radiotherapy (with surgery). A statistically significant difference was shown for disease-free survival (hazard ratio 0.77, 95% confidence interval (CI): 0.64 to 0.92) and total mortality (hazard ratio 0.78, 95% CI: 0.64 to 0.95) in favour of the concomitant chemotherapy and radiotherapy (with surgery) arm. No other treatment regimens showed consistent statistically significant results across the outcomes measured. AUTHORS' CONCLUSIONS: There is some evidence that concomitant radio/chemotherapy (with surgery) is more effective than radiotherapy (with surgery) and may benefit outcomes in patients with more advanced oral and oropharyngeal cancers. As these trials were based on head and neck studies, future studies should evaluate this treatment regimen specifically in oral and oropharyngeal cancers separately and also address tumour staging and its impact on outcomes. In general, future studies are encouraged to evaluate site-specific and stage-specific data for oral and oropharyngeal cancers. Future trials should include health-related quality of life assessment as an outcome measure. There is a need for a consolidated standardised approach to reporting adverse events.

Intraoral Spitz naevus: a case report.

Intraoral occurrences of Spitz naevus are very rare, there being only one previously documented case in the literature. Here is reported a case of a young male who presented with a pigmented lesion of the upper labial mucosa which had the clinical appearance of a simple naevus. Excision biopsy confirmed this to be a Spitz naevus. This lesion shares histopathological similarities with malignant melanoma. Spitz naevus is a benign lesion, but malignant transformation has been reported and close monitoring is recommended.

Screening programmes for the early detection and prevention of oral cancer.

BACKGROUND: Screening programmes for major cancers, such as breast and cervical cancer have effectively decreased the mortality rate and helped to reduce the incidence of these cancers. Although oral cancer is a global health problem with increasing incidence and mortality rates, no national population-based screening programmes for oral cancer have been implemented. To date there is debate on whether to employ screening methods for oral cancer in the daily routine work of health providers. OBJECTIVES: To assess the effectiveness of current screening methods in decreasing oral cancer mortality. SEARCH STRATEGY: Electronic databases (MEDLINE, CANCERLIT, EMBASE, the Cochrane Central Register of Controlled Trials; 1966 to July 2005, The Cochrane Library - Issue 3, 2005), bibliographies, handsearching of specific journals and contact authors were used to identify published and unpublished data. SELECTION CRITERIA: Randomised controlled trials of screening for oral cancer or precursor oral lesions using visual examination, toluidine blue, fluorescence imaging or brush biopsy. DATA COLLECTION AND ANALYSIS: The search found 112 citations and these have been reviewed. One randomised controlled trial of screening strategies for oral cancer was identified as meeting the review's inclusion criteria. Validity assessment, data extraction and statistics evaluation were undertaken by two independent review authors. MAIN RESULTS: One 10-year randomised controlled trial has been included (n = 13 clusters: 191,873 participants). There was no difference in the age-standardised oral cancer mortality rates for the screened group (16.4/100,000 person-years) and the control group (20.7/100,000 person-years). Interestingly, a significant 34% reduction in mortality was recorded in high-risk subjects between the intervention cohort (29.9/100,000 person-years) and the control arm (45.4/100,000). However, this study has some methodological weaknesses. Additionally, the study did not provide any information related to costs, quality of life or even harms of screening from false-positive or false-negative findings. AUTHORS' CONCLUSIONS: Given the limitation of evidence (only one included randomised controlled trial) and the potential methodological weakness of the included study, it is valid to say that there is insufficient evidence to support or refute the use of a visual examination as a method of screening for oral cancer using a visual examination in the general population. Furthermore, no robust evidence exists to suggest that other methods of screening, toluidine blue, fluorescence imaging or brush biopsy, are either beneficial or harmful. Future high quality studies to assess the efficacy, effectiveness and costs of screening are required for the best use of public health resources. In addition, studies to elucidate the natural history of oral cancer, prevention methods and the effectiveness of opportunistic screening in high risk groups are needed. Future studies on improved treatment modalities for oral cancer and precancer are also required.

Deletion mapping on the short arm of chromosome 3 in squamous cell carcinoma of the oral cavity.

Loss of heterozygosity indicative of the presence of tumor suppressor genes on chromosome 3p is commonly observed in carcinomas of various tissues. We have examined loss of heterozygosity on chromosome 3p in 27 oral squamous cell carcinomas using 15 highly informative microsatellite polymorphisms and constructed a deletion map of chromosome 3p. Overall, loss of heterozygosity at one or more loci was observed in 14 tumors (approximately 52%). A majority of these tumors (86%) show loss in more than one area. Three distinct regions were identified: 3p13-3p21.1, 3p21.3-3p23, and 3p25. These data suggest a role for at least three tumor suppressor genes on chromosome 3p in oral squamous carcinomas. The regions of deletions overlap with those described for carcinomas of other tissues and parallel those observed in lung carcinomas. This may reflect the common etiology of the two cancers.

Allelic imbalance on chromosome 3p in oral dysplastic lesions: an early event in oral carcinogenesis.

We have demonstrated previously a loss of constitutional heterozygosity on the short arm of chromosome 3 in approximately 50% of oral squamous cell carcinomas. In the present study, we have investigated 30 oral dysplastic lesions (DLs), presenting clinically as either erythroplakias or leukoplakias with histopathological features of either severe epithelial dysplasia or carcinoma in situ, for LOH on chromosome 3p using 15 microsatellite markers. Thirteen of the 30 LDs (approximately 43%) showed allelic imbalance at one or more loci. The pattern of loss in these lesions defined three noncontiguous regions of interstitial deletions that overlap with those defined for oral squamous cell carcinomas. These data indicate that the alteration of tumor suppressor genes on chromosome 3p is probably an early event in oral carcinogenesis. Additionally, 7 of the 30 DLs showed microsatellite instability. However, the frequency of loci showing microsatellite instability per lesion was low.

Initiating and imaging the coherent surface dynamics of charge carriers in real space.

The tip of a scanning tunnelling microscope is an atomic-scale source of electrons and holes. As the injected charge spreads out, it can induce adsorbed molecules to react. By comparing large-scale 'before' and 'after' images of an adsorbate covered surface, the spatial extent of the nonlocal manipulation is revealed. Here, we measure the nonlocal manipulation of toluene molecules on the Si(111)-7 × 7 surface at room temperature. Both the range and probability of nonlocal manipulation have a voltage dependence. A region within 5-15 nm of the injection site shows a marked reduction in manipulation. We propose that this region marks the extent of the initial coherent (that is, ballistic) time-dependent evolution of the injected charge carrier. Using scanning tunnelling spectroscopy, we develop a model of this time-dependent expansion of the initially localized hole wavepacket within a particular surface state and deduce a quantum coherence (ballistic) lifetime of ∼10 fs.