High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity.

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in prostate cancer as well as in the neo-vasculature of nonprostatic solid tumors. Here, we determined the expression pattern of PSMA in the vasculature of oral squamous cell carcinoma. Using a previously validated antibody, PSMA staining distribution and cyclooxygenase 2 (COX2) expression status was evaluated in a cohort of patients with squamous cell carcinoma of the oral cavity (n=96) using immunohistochemistry and was correlated with clinicopathological features as well as outcome. Twenty-four (25%) cases showed no detectable PSMA staining, 48 (50%) demonstrated positive immunoreactivity for PSMA in less than 50% of microvessels and 24 (25%) cases showed strong endothelial PSMA expression in more than 50% of tumor-associated microvessels. High endothelial PSMA expression was associated with greatly reduced survival (18.2 vs 77.3 months; P=0.0001) and maintained prognostic significance after adjusting for grade and stage in multivariate analysis (hazard ratio=2.19, P=0.007). Furthermore, we observed a strong association between endothelial PSMA and cancer cell-specific COX2 expression. In conclusion, we provide the first evidence for the prognostic significance of endothelial PSMA expression in oral squamous cell carcinoma and, suggest a potential interaction between arachidonic acid metabolites and endothelial PSMA expression in the tumor neo-vasculature.

Facial trauma: how dangerous are skiing and snowboarding?

PURPOSE: The aim of this study was to investigate maxillofacial injuries sustained in both skiing and snowboarding accidents and correlate injury mechanisms and patterns evaluating a large population. MATERIALS AND METHODS: Between 1991 and 2003, all patients with maxillofacial injuries due to skiing and snowboarding accidents (1,393 cases) were reviewed and statistically analyzed according to age, gender, type of injury, cause of accident, location of trauma, and associated injuries. RESULTS: Skiing accidents resulted in a total of 1,250 injuries, and snowboarding resulted in 143. In this study 686 skiers presented with 1,452 facial bone fractures and 80 snowboarders sustained 160 fractures of the face. Skiers had dentoalveolar trauma in 810 cases and 1,295 soft tissue injuries, whereas snowboarders had 88 dental injuries and 187 soft tissue lesions. Mechanisms of injury included 542 cases due to skiing and 85 falls due to snowboarding (a 1.79-fold higher risk for snowboarders). The gender distribution showed a male-female ratio of 3:1 in skiers and 5.5:1 in snowboarders. In both groups male patients were more prone to have a facial bone fracture than female patients. Snowboarders aged between 10 and 29 years had a 2.14-fold higher risk of sustaining a maxillofacial injury than skiers. CONCLUSIONS: In both groups facial bone fractures occurred more often in male patients, and they were more likely to result from falls and collisions with other persons. Young snowboarders had a higher risk of maxillofacial injuries (especially soft tissue lesions) than skiers, whereas for children and old persons, skiing posed a much higher risk. Wearing a helmet while skiing and snowboarding should be mandatory to prevent serious trauma to the head.

The role of oxygen termination of nanocrystalline diamond on immobilisation of BMP-2 and subsequent bone formation.

Medical implants are increasingly often inserted into bone of frail patients, who are advanced in years. Due to age, severe trauma or pathology-related bone changes, osseous healing at the implant site is frequently limited. We were able to demonstrate that coating of endosseous implants with nanocrystalline diamond (NCD) allows stable functionalization by means of physisorption with BMP-2. Strong physisorption was shown to be directly related to the unique properties of NCD, and BMP-2 in its active form interacted strongly when NCD was oxygen-terminated. The binding of the protein was monitored under physiological conditions by single molecule force spectroscopy, and the respective adsorption energies were further substantiated by force-field-calculations. Implant surfaces refined in such a manner yielded enhanced osseointegration in vivo, when inserted into sheep calvaria. Our results further suggest that this technical advancement can be readily applied in clinical therapies with regard to bone healing, since primary human mesenchymal stromal cells strongly activated the expression of osteogenic markers when being cultivated on NCD physisorbed with physiological amounts of BMP-2.

EpCAM expression in squamous cell carcinoma of the oral cavity: frequency and relationship to clinicopathologic features.

This retrospective study was designed to investigate the prognostic significance of EpCAM expression in human oral squamous cell carcinoma on a long-term follow-up. EpCAM expression was examined immunohistochemically on a tissue microarray (TMA) of paraffin embedded tissue specimens from 77 consecutive patients who underwent surgical treatment for squamous cell carcinoma of the oral cavity in the period between 1980 and 1997 at the Department of Craniomaxillofacial and Oral Surgery, Innsbruck Medical University. High EpCAM expression was found in 17 (22.1%) of the tumor samples. Using Kaplan-Meier analysis no correlation of EpCAM overexpression was observed with conventional clinicopathologic features in this patient cohort. Taken together, these data suggest that EpCAM might become an attractive treatment target in a subgroup of patients with OSCC.

Traumatic intracranial haemorrhage in conscious patients with facial fractures--a review of 1959 cases.

OBJECTIVE: Facial fracture patients who are conscious with a Glasgow Coma Scale (GCS) score of 15 in the absence of clinical neurological abnormalities are commonly not expected to have suffered severe intracranial pathology. However, high velocity impact may result in intracranial haemorrhage in different compartments. METHODS: Over a 7-year period, 1959 facial fracture patients with GCS scores of 15 and the absence of neurological abnormalities were analysed. In 54 patients (2.8%) computed tomography scans revealed the presence of accompanying intracranial haemorrhage (study group). These patients were compared with the 1905 patients without intracranial haemorrhage (control group). RESULTS: Univariate analysis identified accompanying vomiting/nausea and seizures, cervical spine injuries, cranial vault and basal skull fractures to be significantly associated with intracranial bleeding. In multivariate analysis the risk was increased nearly 25-fold if an episode of vomiting/nausea had occurred. Seizures increased the risk of bleeding more than 15-fold. The mean functional outcome of the study group according to the Glasgow Outcome Scale was 4.7+/-0.7. CONCLUSION: Intracranial haemorrhage cannot be excluded in patients with facial fractures despite a GCS score of 15 and normal findings following neurological examination. Predictors, such as vomiting/nausea or seizures, skull fractures and closed head injuries, enhance the likelihood of an intracranial haemorrhage and have to be considered.

High EGFR expression predicts poor prognosis in patients with squamous cell carcinoma of the oral cavity and oropharynx: a TMA-based immunohistochemical analysis.

This retrospective study was designed to investigate the prognostic significance of EGFR overexpression in human oral squamous cell carcinoma on a long-term follow-up. EGFR expression was examined immunohistochemically on a tissue microarray (TMA) of paraffin embedded tissue specimens from 109 patients who underwent surgical treatment for squamous cell carcinoma of the oral cavity and oropharynx in the period between 1980 and 1997. High EGFR expression was found in 80 (73.42%) of the tumour samples. Kaplan-Meier curves showed that EGFR overexpression was significantly related to decreased overall survival (p=0.05). Multivariate analysis showed that EGFR overexpression is an independent prognostic marker in these patients (p=0.02, RR 3.6). These results confirm that EGFR overexpression is an independent prognostic marker in patients with squamous cell carcinoma of the oral cavity and oropharynx. The EGFR antigen represents an attractive target for targeted therapies with monoclonal antibodies or specific tyrosine-kinase inhibitors in these patients.

Overexpression of eIF3a in Squamous Cell Carcinoma of the Oral Cavity and Its Putative Relation to Chemotherapy Response.

The eukaryotic translation initiation factor eIF3a is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. It is known to play an important role in general translation initiation as well as in the specific translational regulation of various gene products, among which many influence tumour development, progression, and the therapeutically important pathways of DNA damage repair. Therefore, beyond its role in protein synthesis, eIF3a is emerging as regulator in tumour pathogenesis and therapy response and, therefore, a potential tumor marker. By means of a tissue microarray (TMA) for histopathological and statistical assessment, we here show eIF3a expression in 103 cases of squamous cell carcinoma of the oral cavity (OSCC), representing tissues from 103 independent patients. A subset of the study cohort was treated with platinum based therapy. Our results show that the 170 kDa protein is upregulated in OSCC and correlates with good overall survival. Overexpressing tumors respond better to platinum-based chemotherapy, suggesting eIF3a as a putative predictive as well as prognostic tumor marker in OSCC.

Are temporomandibular joint disk displacements without reduction and osteoarthrosis important determinants of mandibular backward positioning and clockwise rotation?

OBJECTIVE: The aim of this study was to estimate whether, in patients with temporomandibular joint (TMJ) arthralgia, the magnetic resonanace imaging (MRI) findings of bilateral TMJ disk displacement without reduction (DDwoR) and/or osteoarthrosis (OA) are determinants of mandibular backward positioning and/or clockwise rotation. STUDY DESIGN: Bilateral MRI of the TMJ was performed in 50 consecutive TMJ arthralgia patients to identify individuals with bilateral TMJ DDwoR and/or OA. Linear and angular cephalometric measurements were taken to apply selected criteria of mandibular backward positioning (FH to Na-Pog <84°, Na-A-Pog >5°, and SNB <75°) and clockwise rotation (FH to OP >13°, MP to FH >35°, and S-Gn to FH >64°). Logistic regression analysis was used to estimate the association between selected MRI and cephalometric parameters. RESULTS: In the age- and gender-adjusted analyses, significant increases in risk of mandibular backward positioning and clockwise rotation occurred with bilateral DDwoR and OA (9.5:1; P = .040). CONCLUSION: In patients with TMJ arthralgia the MRI parameters of DDwoR and OA seem to be important determinants of mandibular backward positioning and clockwise rotation.

Expression and prognostic impact of indoleamine 2,3-dioxygenase in oral squamous cell carcinomas.

Indoleamine 2,3 dioxygenase (IDO) is a negative immune regulator and was found to be a prognostic marker in several tumor entities. In this study, we analysed IDO expression in oral squamous cell carcinoma (OSCC) regarding patient's prognosis. Additionally, expression of IDO like-1 gene (INDOL-1) was analysed. Tumor tissue from 88 patients with OSCC was analysed by immunohistochemistry for IDO expression. The influence of IDO expression on survival was studied by multivariate Cox regression, adjusting for established clinical prognostic parameters. Real time PCR of tumor samples was performed in a subgroup of patients to analyse mRNA expression of IDO and INDOL-1. IDO high-expression was observed in 44.2% of OSCC patients. No significant correlation was found between IDO expression and clinical stage, sex, age, tumor site, tumor size, metastasis or tumor grade. The median overall survival time was 3.1 years for patients with IDO low tumors, compared to 1.36 years for IDO high tumors (P=.028). Subset analysis of patients receiving adjuvant radio-chemotherapy showed a significant difference (P=.0046) in overall survival between IDO low tumors (3.35 years) and IDO high tumors (1.26 years). In contrast, the impact of IDO expression on survival time in patients without adjuvant therapy was not significant (P=.574). Interestingly, INDOL-1 was not expressed in OSCC. IDO high expression represents a significant negative prognostic factor in patients with OSCC, especially in those patients undergoing adjuvant radiochemotherapy. Our data support the suggestion, co-administration of small-molecule IDO inhibitors could represent a promising new strategy to increase the anti-tumor activity of radio-chemotherapy in patients with IDO positive OSCC.

Prognostic significance of 14-3-3sigma expression in oral squamous cell carcinoma (OSCC).

14-3-3sigma an intracellular phosphoserine binding protein regulates different cellular signalling processes and is involved in cancer development. In this study, we examined the expression of 14-3-3sigma and evaluated its clinical significance in OSCC. Tumour tissue from 95 OSCC patients was analysed for 14-3-3sigma and p53 expression, respectively. The correlation of these proteins with survival and clinical parameters was assessed. 14-3-3sigma high expression was observed in 44.2% of OSCC patients. A significant role of 14-3-3sigma expression on survival was shown by Kaplan-Meier analysis. Median survival time was 4.1years for patients with 14-3-3sigma low tumours, compared with 1.36years for 14-3-3sigma high tumours (P=.0021). Subset analysis in patients receiving adjuvant chemotherapy showed that the overall survival was significantly decreased in 14-3-3sigma high tumours than in 14-3-3sigma low tumours (P=.02). p53 expression was not significant in univariate analyses. In multivariate regression analysis, 14-3-3sigma expression emerged as a significant independent parameter (P=.003). These results provide evidence that 14-3-3sigma expression is involved in OSCC and, in contrast to p53 expression represents a new prognostic marker for OSCC and therapy response. Pending validation targeting 14-3-3sigma might also be a new opportunity to improve therapy.

Characteristics of pulpal blood flow levels associated with non-segmented and segmented Le Fort I osteotomy.

OBJECTIVES: Laser Doppler flowmetry (LDF) is a noninvasive method to assess pulpal blood-flow (PBF). The purpose of this study was (1) to test whether Le Fort I (LF-I) osteotomy may show tooth type-related effects on LDF measurements, and (2) to investigate whether LF-I and tooth type may predict adverse PBF outcomes. MATERIAL AND METHODS: PBF was recorded bilaterally in maxillary incisors, canines, and first premolars in a surgical group of patients who underwent a segmented (n = 14) or nonsegmented LF-I osteotomy (n = 12), and in a nonsurgical group of control subjects (n = 12) who did not undergo orthodontic treatment. PBF measurements were made before surgery (session I), and at intervals between 3 and 5 days (session II), and 55 and 59 days after surgery (session III). The nonsurgical control subjects were tested at similar intervals. An adverse outcome was defined as the presence of "PBF reduction of > 40%." Statistical analysis consisted of univariate analysis of variance for repeated measurements. A multiple logistic regression analysis was used to compute the odds ratio for LF-I and tooth type for adverse outcome versus nonadverse outcome. RESULTS: For the LF-I osteotomy study group there was a significant change in PBF values (P = .000). Analysis of session-related measurements revealed a significant difference between session I- and II-related measurements for the canine (P = .004) of the segmented LF-I osteotomy. Significant increase in risk of a session II-related adverse outcome occurred with a nonsegmented (16.6 odds ratio) (P = .009) and segmented LF-I osteotomy (59.2 odds ratio) (P = .000). The odds ratio that a patient with a segmented LF-I osteotomy might belong to the session III-related adverse outcome group was strong (20.6) and significant (P = .007). CONCLUSIONS: LF-I osteotomy type proved to be linked to changes in tooth type-related LDF measurements; it was an important prognostic determinant of adverse PBF outcomes.

TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity.

Squamous cell carcinoma is by far the most common type of cancer of the oral cavity, representing more than 90% of all oral cancers. Despite refinement of surgical techniques and adjuvant therapies, the prognosis for patients with oral squamous cell carcinoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment. Recently, the human trophoblast cell-surface antigen TROP2 was found to be highly expressed in colorectal cancer, correlating with aggressiveness and poor prognosis. Thus, the aim of this study was to investigate TROP2 expression and its prognostic impact in oral squamous cell carcinoma patients. TROP2 expression was examined by immunohistochemistry in a series of 90 patients on a tissue microarray of paraffin-embedded specimens. Survival was calculated using Kaplan-Meier estimates. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 52 (58%) of the tumor samples. Kaplan-Meier curves showed that TROP2 overexpression was significantly associated with decreased overall survival (P<0.01). Overall survival gradually worsened with increasing TROP2 scores. By univariate analyses, no correlation with conventional clinicopathological features was found. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent factor predictive of poor disease outcome (P<0.01). These results demonstrate that TROP2 overexpression is an independent prognostic marker in patients with oral squamous cell carcinoma. TROP2 overexpression was detectable in 58% of the tumor samples, indicating it to be a potential novel therapeutic target in squamous cell carcinoma of the oral cavity.

STAT1 activation in squamous cell cancer of the oral cavity: a potential predictive marker of response to adjuvant chemotherapy.

BACKGROUND: For patients with squamous cell carcinoma of the oral cavity, both locoregional and distant recurrences are common, and an appropriate adjuvant treatment modality has yet to be defined. Thus, there is an urgent need to identify novel molecular markers with potential prognostic and/or predictive value to improve treatment outcome in these patients. This retrospective study was designed to investigate the predictive and/or prognostic value of STAT1 activation in squamous cell carcinoma of the oral cavity. METHODS: STAT1 expression and subcellular localization was examined immunohistochemically on a tissue microarray of paraffin-embedded tumor specimens from 89 patients who underwent surgical treatment in the period between 1980 and 1997. A nuclear staining score of greater than 35% was defined as high STAT1 activation. RESULTS: According to study criteria, 18% of analyzed tumor samples exhibited high STAT1 activation. High STAT1 activation was associated with negative lymph node status. Moreover, in the subgroup of patients who received chemotherapy, high nuclear STAT1 staining in the tumor was associated with good prognosis. CONCLUSIONS: This is the first report demonstrating the potential predictive value of STAT1 activation status in patients with squamous cell cancer of the oral cavity. If confirmed in large prospective trials, this molecular marker could help in guiding therapeutic decisions in these patients.

A reason for the use of toluidine blue staining in the presurgical management of patients with oral squamous cell carcinomas.

Verification of oral cancer relies on histopathological diagnosis of suspect or malignant lesions. There is evidence for further pre-surgical screening procedures to localize tumor borders and define other malignant lesions. Important methods are: visual examination, including pan-endoscopy, fluorescence imaging, and brush biopsy, as well as radiologic techniques such as conventional radiography, computed tomography, magnetic resonance imaging, scintigraphy, and ultrasonography, which may reduce the mortality rate associated with oral cancer. In addition, toluidine blue staining is a simple, inexpensive, and excellent diagnostic tool. Herein we show that the clinical use of in vivo staining is effective to define the superficial tumor borders and to detect malignant or pre-malignant cells in the surrounding area of the tumor following detection of a malignancy of the oral cavity. In our reported case, the main tumor mass was surrounded by layers of an intact mucosa, yet in a distance of more than 1 cm a group of malignant or pre-malignant cells in the surrounding area required a resection of the tumor in a size that would have been unaddressed during visual examination alone followed by clinical routine program of presurgical examinations after the detection of a malignancy of the oral cavity.