[Importance of interdisciplinary collaboration for optimal treatment of orbital tumors]. / Bedeutung der interdisziplinären Zusammenarbeit für eine optimale Behandlung orbitaler Tumoren.

Optimal treatment of tumors with orbital invasion may exceed the competences of an individual medical specialty and require interdisciplinary cooperation. The aim of this article is to present an interdisciplinary treatment concept based on the examples of intraorbital hemangioma and squamous cell carcinoma of the paranasal sinuses infiltrating the orbit. In addition to a detailed medical history and a complete ophthalmological examination, a detailed imaging technique with standardized echography and tomography methods such as orbital thin-slice CT and/or in many cases MRI is essential for the primary classification of an intraorbital pathology. Depending on the type of pathology, a purely surgical procedure involving various disciplines such as ophthalmology, otorhinolaryngology, maxillofacial surgery, neurosurgery, and pathology, or an interdisciplinary treatment regimen including (neo)adjuvant radiotherapy or chemotherapy is necessary. Orbital tumors have a wide range of potential pathologies, requiring complex surgical procedures and multimodal therapies. In case of infiltration of the paranasal sinuses or intracranial structures, an interdisciplinary team including neuroradiologists, oral-maxillofacial surgeons, otorhinolaryngologists, neurosurgeons, radiation therapists, ophthalmologists, pathologists, oncologists, and psycho-oncologists is essential for successful treatment.

The prognostic relevance of lymph node ratio in patients with oral squamous cell carcinoma treated with neoadjuvant therapy regimen and radical surgery.

BACKGROUND: This study aims at investigating the prognostic significance of lymph node ratio (LNR) in a cohort of patients with oral squamous cell carcinomas (OSCC), treated with neoadjuvant radiochemotherapy followed by radical surgery. METHODS: The study included 171 treatment-naive patients with biopsy-proven primary OSCC, being reviewed retrospectively. All patients received a concomitant neoadjuvant radiochemotherapy (RCT) followed by radical surgery of the primary tumor and neck dissection based on the pretreatment staging results. The Kaplan-Meier survival analysis method was used to estimate the events of interest for overall survival (OS). Prognostic factors were identified through univariate and multivariate analysis. RESULTS: The 5-year overall survival rate for all patients was 48 %. In univariate analysis, patient's age and data compiled from the histopathological examination as margin status, extracapsular spread, ypT, ypN, ypUICC, number of positive lymph nodes and lymph node ratio (LNR) had a statistically significant impact on overall survival. Multivariate analysis revealed an independent significant impact of patient age, ypT, margin status and LNR on OS. ypN showed no statistical significant impact on OS. CONCLUSION: Our results show that LNR is an important predictor for OS in patients with OSCC that were treated with neoadjuvant radiochemotherapy and radical surgery.

Ameloblastoma-Clinical, radiological, and therapeutic findings.

Ameloblastoma are the most common odontogenic tumor. As they usually do not form metastasis, they are considered as benign tumors with a locally invasive growth pattern and destruction of the jaws and the surrounding tissue (Oral Diseases, 23, 2017, 199). This article focuses on clinical, radiological, and therapeutic findings, which may influence diagnosis and treatment of ameloblastoma in the future.

Distance-dependent accuracy in Le Fort I maxillary repositioning procedures.

It has been hypothesised that, in maxillary repositioning procedures, longer distances correlate with less accurate transfers and particularly the repositioning forces of facial skin and muscles that increase exponentially. However, this has not to our knowledge been confirmed. The purpose of this study was to search for differences in the accuracy of transfer from maxillary repositioning procedures parallel to the three orthogonal planes and with respect to three different anatomical landmarks of the first molar left and right (M1L and M1R) and the first incisor (I). Cone-beam computed tomography (CT) datasets taken before and after operation for 92 patients who had Le Fort I maxillary repositioning procedures were aligned to measure the changes in the maxillary position in the axial, sagittal, and transverse directions. Differences between planned distances and those achieved were calculated and analysed with Pearsons correlation coefficient. The strongest significant correlations between the extent of planned repositioning distances and achieved differences (error) were detected in the sagittal plane for the anatomical landmarks of the right (M1R) and left first molar (M1L). Correlations became weaker if a limited planned distance ranging from 0-4mm was compared with a complete observed range that reached up to 12mm. Our results show for the first time to our knowledge that the accuracy of transfer of wafer-based maxillary positioning procedures depends on the distance being moved. Longer distances correlate with less accuracy, particularly in the sagittal plane and in the first molar region.

Prediction of outcome by lymph node ratio in patients with parotid gland cancer.

OBJECTIVE: Lymph node ratio (LNR) has been shown to be an independent predictor of recurrence risk and survival in different entities of carcinoma. METHODS: In this retrospective chart review, 128 patients with parotid gland cancer (PGC) subsequently treated by primary surgery were included. About 64% (n = 82) of these patients were additionally treated with adjuvant radiotherapy. Five-year overall survival rates were determined by subgroups based on LNR value. RESULTS: Lymph node ratio was found to be significantly associated with overall survival rate (P < 0.001). Using univariate analyses, pathological tumour-node-metastasis (TNM)-stage, UICC-stage grouping and extracapsular spread were found to be significant predictors of overall survival (P < 0.001). However, with a multivariate analyses, LNR remained the only independent predictor of overall survival (P = 0.043). CONCLUSIONS: After surgery for PGC, evaluation of the neck using LNR was found to reliably stratify the overall survival rate.

Three-dimensional cone beam computed tomography analysis of maxillary sinus and alveolar bone anatomy in the restorative axis of dental implants using radiopaque drill guides.

The objectives were to assess the sinus anatomy and alveolar ridge dimensions and to identify clinical factors and morphological relationships that may predict the characteristics of the sinus anatomy. A total 336 edentulous molar and 168 edentulous premolar regions were analyzed. The mediolateral maxillary sinus (5mm and 10mm above alveolar bone), lateral maxillary sinus wall, ostium height, and alveolar ridges were measured. Measurement regions were defined by radiopaque simulation of the restoration goal. Mean molar mediolateral dimensions were >10mm: first molar, 11.8mm (range 3.8-21.1mm); second molar, 12.2mm (range 7.9-20.1mm). The extent of the sinus differed significantly between premolars and molars (P<0.001). The first molar region had the highest mean value for the lateral sinus wall (2.4mm, range 0.2-7.9mm) and the greatest distance between the alveolar crest and simulated restorative goal (8.1mm, range 1.1-16.3mm). Septum prevalence was 46% in the molar region and 27% in the premolar region. A lower alveolar ridge height was associated with a wider transverse extent of maxillary sinus and consequently longer distances between the crest and restorative goal. Systematic three-dimensional analysis of the maxillary sinus yields precise preoperative information about sinus configurations. There were significant variations and relationships among characteristics of the maxillary sinus, ridge, and the restorative goal.

Three-dimensional fracture pattern analysis of the Obwegeser and Dal Pont bilateral sagittal split osteotomy.

The Obwegeser and Dal Pont modification of the bilateral sagittal split osteotomy (BSSO) is a well-established procedure in orthognathic surgery. The purpose of this retrospective study was to analyze the actual fracture patterns achieved with BSSO by Obwegeser and Dal Pont modification using postoperative cone beam computed tomography (CBCT) datasets from 100 patients. A total of 200 split osteotomies were assessed, which could be categorized into nine different split patterns. Only one of the observed split fractures (0.5%) followed exactly the fracture line described by Obwegeser and Dal Pont, whereas 40% followed the fracture line according to the Hunsuck and Epker modification and 13.5% were seen as unfavourable splits mainly running over the buccal plate. A significant correlation was found between unfavourable buccal splits and both horizontal osteotomies reaching the buccal surface at the dorsal ramus (P=0.001) and a vertical caudal bone cut end at the corpus with a buccal position (P<0.001). These results show that a complete antero-posterior horizontal osteotomy at the mandibular ramus does not lead to the intended fracture pattern, which rebuts the argument of a greater amount of bony overlap using the Obwegeser and Dal Pont modification.

Prognostic Performance of Current Stage III Oral Cancer Patients After Curative Intent Resection: Evidence to Support a Revision of the American Joint Committee on Cancer Staging System.

BACKGROUND: The American Joint Committee on Cancer (AJCC) stage III classification of oral cavity squamous cell carcinoma (OCSCC) represents a heterogeneous group of patients with early local disease with regional metastases (T1N1 and T2N1) and advanced local disease with or without regional metastasis (T3N0 and T3N1). OBJECTIVE: The aim of this study was to evaluate prognostic heterogeneity in the stage III category. METHODS AND PATIENTS: An international retrospective multicenter study of 1815 patients who were treated for OCSCC from 2003 to 2011. RESULTS: Kaplan-Meier survival analysis and multivariate models of stage III patients revealed better overall survival (OS; HR 2.12, 95 % CI 1.03-4.15; p = 0.01) and disease-specific survival (DSS; HR 1.7, 95 % CI 1.16-4.12; p = 0.04) rates for patients with T1-2N1/T3N0 disease than for patients with T3N1 disease. The outcomes of patients with T3N1 and stage IVa disease were similar (p = 0.89 and p = 0.78 for OS and DSS, respectively). Modifying stage classification by transferring the T3N1 category to the stage VIa group resulted in a better prognostic performance [Harrell's concordance index, C index 0.76; Akaike's Information Criterion (AIC) 4131.6] compared with the AJCC 7th edition staging system (C index 0.65; AIC 4144.9) for OS. When DSS was assessed, the suggested staging system remained the best performing model (C index 0.71; AIC 1061.3) compared with the current AJCC 7th edition staging (C index 0.64; AIC 1066.2). CONCLUSIONS: The prognosis of T3N1 and stage IVa disease are similar in OCSCC, suggesting that these categories could be combined in future revisions of the nodal staging system to enhance prognostic accuracy.

Histopathological assessment of tumour regression, nodal stage and status of resection margins determines prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy.

OBJECTIVES: In advanced oral squamous cell carcinoma (OSCC), tumour regression after neoadjuvant radiochemotherapy seems to be an important prognostic factor. In this study, we intended to compare regression grading according to two previously described regression models and to analyse the association of tumour regression and other tumour characteristics with patients' characteristics and overall survival. METHODS: The retrospective study included 63 treatment-naive patients with primary OSCC of stages II-IV, who were treated with a concomitant neoadjuvant radiochemotherapy followed by radical surgery. Assessment of histopathological features was performed, there under regression grading according to two previously described regression models. RESULTS: Both tumour regression models provided comparable results in terms of distribution of different regression grades. In univariate analysis regression gradings (P = 0.003 and P = 0.007), ypT-stage, ypN-stage and status of resection margins (P < 0.001) were significantly associated with the 5-year overall survival (OS). None of the pretreatment clinicopathological parameters showed association with histopathological tumour regression. Multivariate analysis revealed the status of resection margins and of lymph node metastasis as statistically significant features for OS (P = 0.020 and P = 0.003, respectively). CONCLUSION: Tumour regression grading, nodal stage and status of resection margins predict prognosis in patients after neoadjuvant treatment. Currently, there are no pretreatment clinicopathological parameters, which predicting good tumour response to therapy. Thus, identifying non-responding patients, which might benefit from an intensified systemic therapy, requires surgical resection and consecutive histopathological assessment. Therefore, further investigation and validation of new, especially, molecular predictors of tumour response to radiochemotherapy remains an unmet, future clinical need.

Lymph node density in oral cavity cancer: results of the International Consortium for Outcomes Research.

BACKGROUND: Lymph node density (LND) has previously been reported to reliably predict recurrence risk and survival in oral cavity squamous cell carcinoma (OSCC). This multicenter international study was designed to validate the concept of LND in OSCC. METHODS: The study included 4254 patients diagnosed as having OSCC. The median follow-up was 41 months. Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional control and distant metastasis rates were calculated using the Kaplan-Meier method. Lymph node density (number of positive lymph nodes/total number of excised lymph nodes) was subjected to multivariate analysis. RESULTS: The OS was 49% for patients with LND0.07 compared with 35% for patients with LND>0.07 (P<0.001). Similarly, the DSS was 60% for patients with LND0.07 compared with 41% for those with LND>0.07 (P<0.001). Lymph node density reliably stratified patients according to their risk of failure within the individual N subgroups (P=0.03). A modified TNM staging system based on LND ratio was consistently superior to the traditional system in estimating survival measures. CONCLUSION: This multi-institutional study validates the reliability and applicability of LND as a predictor of outcomes in OSCC. Lymph node density can potentially assist in identifying patients with poor outcomes and therefore for whom more aggressive adjuvant treatment is needed.

Clinical nodal stage is a significant predictor of outcome in patients with oral cavity squamous cell carcinoma and pathologically negative neck metastases: results of the international consortium for outcome research.

BACKGROUND: We aimed to study the importance of clinical N classification (cN) in a subgroup of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically negative neck nodes (pN-). METHODS: A total of 2,258 patients from 11 cancer centers who underwent neck dissection for OSCC (1990-2011) had pN- disease. The median follow-up was 44 months. 5-year overall survival (OS), disease-specific survival (DSS), disease free survival, local control, locoregional control, and distant metastasis rates were calculated by the Kaplan-Meier method. cN classification and tumor, node, metastasis classification system staging variables were subjected to multivariate analysis. RESULTS: A total of 345 patients were preoperatively classified as cN+ and 1,913 were classified as cN-. The 5-year OS and DSS of cN- patients were 73.6 and 82.2 %, respectively. The 5-year OS and DSS of cN+ patients were 64.9 and 76.9 %, respectively (p < 0.0001 each). A cN+ classification was a significant predictor of worse OS (p = 0.03) and DSS (p = 0.016), regardless of treatment, depth of invasion, or extent of neck dissection. cN classification was associated with recurrence-free survival (p = 0.01) and locoregional (neck and primary tumor) control (p = 0.004), but not with local (p = 0.19) and distant (p = 0.06) recurrence rates. CONCLUSIONS: Clinical evidence of neck metastases is an independent predictor of outcome, even in patients with pN- nodes.

Podoplanin expression in oral leukoplakia: prognostic value and clinicopathological implications.

OBJECTIVES: Current clinicopathological parameters cannot predict the risk of malignant transformation in oral leukoplakia sufficiently. Recent studies have shown that podoplanin is expressed in oral cancer and precancerous lesions. The aim of our study was to assess whether podoplanin expression in pretreatment biopsies could serve as a biomarker to predict the risk of malignant transformation in patients with oral leukoplakia. MATERIALS AND METHODS: In this retrospective study, podoplanin expression was analysed in 60 patients with previously untreated oral leukoplakia by immunohistochemistry. We investigated the associations between podoplanin expression and various clinicopathological variables including oral cancer-free survival (OCFS) and the SIN-classification. RESULTS: The chi-square-test revealed that high expression of podoplanin in pretreatment biopsies was associated with malignant transformation (P = 0.003) and increasing SIN-classification (P = 0.009). In univariate analysis, podoplanin expression in oral leukoplakia had a significant impact on OCFS (P = 0.009). The 5-year OCFS rate decreased from 100% for patients with no podoplanin expression to 41.7% for patients with the highest level of podoplanin expression. CONCLUSION: Although podoplanin expression and the SIN-classification served as factors to predict malignant transformation in patients with oral leukoplakia in univariate analysis, no significant impact was found for both factors in multivariate analysis.

O-GlcNAcylation is involved in the transcriptional activity of EWS-FLI1 in Ewing's sarcoma.

The oncogene EWS-FLI1 encodes a chimeric transcription factor expressed in Ewing's sarcoma family tumors (ESFTs). EWS-FLI1 target gene expression is thought to drive ESFT pathogenesis and, therefore, inhibition of EWS-FLI1 activity holds high therapeutic promise. As the activity of many transcription factors is regulated by post-translational modifications, we studied the presence of modifications on EWS-FLI1. The immuno-purified fusion-protein was recognized by an antibody specific for O-linked beta-N-acetylglucosaminylation, and bound readily to a phosphoprotein-specific dye. Inhibition of Ser/Thr-specific phophatases increased EWS-FLI1 molecular weight and reduced its O-GlcNAc content, suggesting that phosphorylation and O-GlcNAcylation of EWS-FLI1 interact dynamically. By mutation analysis, O-GlcNAcylation was delineated to Ser/Thr residues of the amino-terminal EWS transcriptional-activation domain. Metabolic inhibition of the hexosamine biosynthetic pathway abrogated O-GlcNAcylation of EWS-FLI1 and interfered specifically with transcriptional activation of the EWS-FLI1 target Id2. These results suggest that drugs modulating glycosylation of EWS-FLI1 interfere functionally with its activity and might, therefore, constitute promising additions to the current ESFT chemotherapy.

Single modality and multimodality treatment of nasal and paranasal sinuses cancer: a single institution experience of 229 patients.

AIMS: To assess the single and multimodal treatment results and prognostic factors for sinonasal carcinoma. METHODS: Overall survival (OS), disease-specific survival (DSS), local control (LC), and disease-free survival (DFS) in 229 patients with sinonasal carcinoma treated from 1967 to 2003 were calculated. Prognostic factors were univariately and multivariately analyzed. The median follow-up period for survivors was 126 months. RESULTS: 32% of the patients were operated only, 47% underwent multimodal therapy, and 20% were treated without operation. The 5-year OS rate was 41%, and the DSS rate was 51%. The LC rate was 64%, and the DFS rate was 34%. Prognostic for DSS were M status (p<0.001), UICC stage (p<0.001), T classification (p=0.001), N status (p=0.002), intracranial tumor infiltration (p=0.008), infiltration of the pterygopalatine fossa (p=0.02), infiltration of the skull base (p=0.021), infiltration of the orbita (p=0.041), and the type of therapy (p<0.001): The 5-year DSS rate was 63% for patients operated only, 56% for all operated patients, 46% for patients undergoing surgery and radiotherapy, but only 21% for patients treated with radiotherapy+/-chemotherapy. Multivariate analysis revealed that T classification (p=0.042), N classification (p=0.035), M classification (p=0.007), UICC stage (p=0.038), and type of therapy (p=0.038) were independent prognostic factors for DSS. CONCLUSIONS: Radical surgery is recommended for stage I/II sinonasal carcinomas. Stage III/IV carcinomas still have a poor prognosis, but multimodal treatment seems to favor the outcome.

Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells.

High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing's sarcoma family of tumors (ESFT). CD99 is a cell surface glycoprotein whose engagement has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins in hematopoietic cells. In ESFT, antibody ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene downregulated by high constitutive CD99 expression in ESFT.