Osteosarcoma of the jaw - experience at the Medical University Vienna and comparative study with international tumor registries.

OBJECTIVES: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens. METHOD: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher's exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry. RESULTS: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients. CONCLUSIONS: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period.

Osteosarcoma of the jaw - experience at the Medical University Vienna and comparative study with international tumor registries

OBJECTIVES: Osteosarcoma of the jaw (OSAJ) is fundamentally different in clinical practice from its peripheral counterparts. Studies are difficult to conduct due to low incidence rates. The primary aim of this study was to provide for the first time a comprehensive retrospective analysis of the treatment concepts and outcome data of OSAJ patients treated at the University Hospital Vienna and to compare these with two recently published studies on OSAJ. The clinical study was accompanied by a biomarker study investigating the prognostic relevance of melanoma-associated antigen-A (MAGE-A) in OSAJ specimens. METHOD: Eighteen patients were included, and their outcomes were compared to published data. Immunohistochemistry was performed with mouse monoclonal antibodies against MAGE-A. Survival rates were estimated by the Kaplan-Meyer method. The log-rank test was used to analyze potential prognostic parameters. Fisher's exact test was performed to define the significant differences between the survival rates of the current study and the DOESAK registry. RESULTS: Disease-specific survival was 93.8% after five and 56.3% after ten years. The development of metastases (p=0.033) or relapse (p=0.037) was associated with worsened outcomes in our group as well as in the comparative group. Despite the different treatment concepts of the study groups, survival rates were comparable. MAGE-A failed to show prognostic relevance for OSAJ patients. CONCLUSIONS: Uncertainties about the optimal treatment strategies of OSAJ patients will currently remain. Thus, prospective studies of OSAJ are needed but are only feasible in a multicenter study setting, conducted over a prolonged time period.

Experience in Intra-arterial Chemotherapy using Two Protocols for the Treatment of OSCC over Two Decades at the University Hospital Vienna.

OBJECTIVES: This retrospective study performed a comprehensive analysis of the usage of intra-arterial chemotherapy (iaCh) for locally recurrent UICC stage IV oral squamous cell carcinoma (OSCC) over two decades at the Department of Cranio-Maxillofacial and Oral Surgery at the University Hospital Vienna to assess the utility of its future use. METHODS: Between 1994 and 2014, iaCh was indicated in 48 OSCC cases. In these, the two most frequent iaCh schemes, cisplatin/5-fluorouracil (Cis/5-FU) and methotrexate/bleomycin (MTX/Bleo), were chosen for further analysis. The effect on survival of two distinct intra-arterial protocols and their covariates were analyzed with the Kaplan-Meier method as well as univariate and multivariate Cox proportional hazard regression models. RESULTS: The mean follow-up period was 29.91 months. The two intra-arterial chemotherapy groups did not differ significantly in sample size, demographic data or therapeutic covariates. The Cis/5-FU iaCh regimen was associated with significantly better overall survival (median OS 2.6 years vs. 1.3 years; p=0.002) and had a beneficial effect on survival (HR=3.62, p=0.015). Side effects occurred at a frequency similar to that described in the literature for intravenous chemotherapy (ivCh). CONCLUSIONS: These results suggest a preference for administering Cis/5-FU for iaCh. Nevertheless, due to economic considerations in healthcare expenditures, there is no future for iaCh in the treatment of head and neck carcinomas because ivCh is known to be equivalent.

Comparative Analysis of Clinical and Pathological Lymph Node Staging Data in Head and Neck Squamous Cell Carcinoma Patients Treated at the General Hospital Vienna.

BACKGROUND: Results from publications evaluating discrepancies between clinical staging data in relation to pathological findings demonstrate that a significant number of head and neck squamous cell carcinoma (HNSCC) patients are not correctly staged. The aim of this retrospective study was to analyze potential discrepancies of radiological assessment versus pathological data of regional lymph node involvement and to compare the results with data published in the literature. PATIENTS AND METHODS: In a retrospective analysis we focused on patients with HNSCC routinely treated by surgery plus postoperative radiotherapy between 2002 and 2012. For inclusion, complete pre-operative clinical staging information with lymph node status and patho-histological information on involved lymph node regions as well as survival outcome data were mandatory. We included 87 patients (UICC stage III-IV 90.8%) for which the aforementioned data obtained by CT or MRI were available. Overall survival rates were estimated by the Kaplan-Meier method. The Pearson correlation coefficient and Spearman's rank correlation coefficient (non-linear relationship) was calculated. RESULTS: Discrepancies at the level of overall tumour stage assessment were noticed in 27.5% of all cases. Thereof, 5.7% were assigned to patho-histological up-staging or down-staging of the primary tumour. At the lymph node level, 11.5% of the patients were downstaged, and 10.3% were upstaged. CONCLUSIONS: The study showed that in approximately one-fifth (21.8%) of the patients, lymph node assessment by CT or MRI differs from the pathologic staging, an outcome that corresponds well with those published by several other groups in this field.

Experience in intra-arterial chemotherapy using two protocols for the treatment of OSCC over two decades at the University Hospital Vienna

OBJECTIVES: This retrospective study performed a comprehensive analysis of the usage of intra-arterial chemotherapy (iaCh) for locally recurrent UICC stage IV oral squamous cell carcinoma (OSCC) over two decades at the Department of Cranio-Maxillofacial and Oral Surgery at the University Hospital Vienna to assess the utility of its future use. METHODS: Between 1994 and 2014, iaCh was indicated in 48 OSCC cases. In these, the two most frequent iaCh schemes, cisplatin/5-fluorouracil (Cis/5-FU) and methotrexate/bleomycin (MTX/Bleo), were chosen for further analysis. The effect on survival of two distinct intra-arterial protocols and their covariates were analyzed with the Kaplan-Meier method as well as univariate and multivariate Cox proportional hazard regression models. RESULTS: The mean follow-up period was 29.91 months. The two intra-arterial chemotherapy groups did not differ significantly in sample size, demographic data or therapeutic covariates. The Cis/5-FU iaCh regimen was associated with significantly better overall survival (median OS 2.6 years vs. 1.3 years; p=0.002) and had a beneficial effect on survival (HR=3.62, p=0.015). Side effects occurred at a frequency similar to that described in the literature for intravenous chemotherapy (ivCh). CONCLUSIONS: These results suggest a preference for administering Cis/5-FU for iaCh. Nevertheless, due to economic considerations in healthcare expenditures, there is no future for iaCh in the treatment of head and neck carcinomas because ivCh is known to be equivalent.

Surgical site infection in clean-contaminated wounds after multimodal treatment of advanced oral squamous cell carcinoma.

OBJECTIVES: The aim of this study was to assess the incidence rate for surgical site infections (SSI), patient- and therapy-related risk factors in UICC stage III and IV oral squamous cell carcinoma patients treated with preoperative radiochemotherapy, ablative surgery and immediate microvascular free flap reconstruction. MATERIAL AND METHODS: This retrospective analysis included 85 patients with oral squamous cell carcinoma treated by neoadjuvant radiochemotherapy, tumor surgery and immediate free flap reconstruction. Patient-, therapy-related factors and blood parameters were collected for this selective cohort. RESULTS: The incidence for SSI was 44.7% and for transplant loss 14.1%. Minor BMI changes (p = 0.010), diabetes (p = 0.003), edentulous status (p = 0.006) and cessation of alcohol consumption (0.034) showed to be significant patient-related risk factors. No therapy-related factors were found to be significantly influencing the risk for SSI. Neutrophil counts (p = 0.027) and GGT (p = 0.002) were found to be significantly linked to SSI. CONCLUSION: The not so common treatment option for oral squamous cell carcinomas showed no more risk for SSI compared to standard treatment options. Preserving the ability for healthy nutrition has a significant impact on the development of SSI. This applies not only to the presented and particular treatment option.

Neoadjuvant radiotherapy plus radical surgery for locally advanced stage III/IV oral cancer: Analysis of prognostic factors affecting overall survival.

OBJECTIVES: Preoperative radiotherapy followed by surgery is an effective treatment option for solid tumors including locally advanced squamous cell cancers of the head and neck region. Histopathologic response to radiation has been shown to be associated with survival. However, the relative prognostic importance of regression grade compared to other potential biomarkers has not been established yet. MATERIALS AND METHODS: One-hundred forty-four oral squamous cell carcinoma patients with stage III/IV disease were included in this analysis. Patients had received preoperative radiotherapy (RT) up to 50Gy total dose in combination with 5-Fluorouracil (5-FU)/Mitomycin C (MMC) or with Cetuximab, followed by radical surgery six to eight weeks later. Outcome data were obtained from the patient's files. Survival rates were estimated by the Kaplan-Meyer method. Cox-proportional-hazard regression models were used to compare the risk of death among patients stratified according to risk factors. RESULTS: Five-year overall survival (OS) was 58% in the presented collective. Regression grade 4 (HR 3.58; p<0.001) was most significantly associated with reduced survival, followed by elevated neutrophils (HR 2.22; p=0.01), the combination of elevated neutrophils plus elevated CRP (HR 2.40; p=0.01), and elevated CRP alone (HR 1.74; p=0.03). In a multivariate analysis, the regression grade remained the most influential predictor of outcome (HR 4.23; p<0.001). CONCLUSION: In a comparative analysis, tumor response to pre-operative radiotherapy remains the strongest prognostic factor for treatment outcome, while elevated CRP, as well as neutrophils, were also found to be of significance.

Clinical Management of Impacted and Transmigrated Lower Canines.

PURPOSE: Impacted, in particular transmigrated, lower canines are rare. If they transmigrate, then the most common treatment is extraction. Alternatively, the native tooth can be preserved; however, management is complex. This report describes a decision-making flowchart (DMFC) with surgical strategies for the management of impacted lower canines. MATERIALS AND METHODS: Fifty-six patients had impacted lower canines, of which 16 were transmigrated. A preliminary version of the DMFC was used for the development of treatment plans to decide which strategy to apply to these complex cases. After removal of associated pathologies (for experimental tooth-preserving therapies), miniscrews were used as transient skeletal anchorage devices (TADs). The TADs allowed a closed surgical approach for impacted and transmigrated lower canine eruption. For autotransplantation, a dummy tooth was used for socket preparation to minimize the period of no blood supply to the graft. RESULTS: After surgical exposure and TAD insertion, orthodontic treatment was performed in 4 patients. One patient was selected for successful autotransplantation. Nine patients had the transmigrated canines surgically removed. The remaining patients opted for "leave and observe." Based on the satisfactory long-term results with orthodontic treatment and autotransplantation and on published reports, the resulting DMFC presents key aspects of the treatment plan, namely 1) associated pathology, 2) patient age, 3) compliance, and 4) root tip position. CONCLUSIONS: TAD-assisted orthodontic treatment and autotransplantation of impacted lower canines are tooth-preserving alternatives to extraction. The developed DMFC assists the complex treatment planning of impacted and transmigrated lower canines.

Causes and timing of delayed bleeding after oral surgery.

OBJECTIVES: This study examines a cohort of patients who suffered bleeding requiring hemostatic intervention after oral surgery. The reasons for bleeding and the interval between surgery and onset of bleeding are investigated. MATERIALS AND METHODS: Between 1998 and 2009, 1,819 cases were eligible for this retrospective study. Factors (independent parameters) influencing the interval (dependent variable) were analyzed using negative binomial count regression models (NegBin II). The significance of each regressor's effect was tested using Wald's test and the total effect using likelihood ratio test. RESULTS: Of the patients examined, 1,101 (60.1 %) did not take anticoagulants, 394 (21.5 %) took phenprocoumon, 233 (12.7 %) took acetylsalicylic acid, 33 (1.8 %) took clopidogrel, 17 (0.9 %) took more than one anticoagulant, and 78 (4.3 %) had a congenital blood disorder. After simple tooth extraction, 95.3 % suffered bleeding; 69.7 % of extractions were performed in the molar region. Later that day of surgery, 66.0 % of all patients showed bleeding. The bleeding interval was significantly prolonged by anticoagulant therapy with phenprocoumon, by congenital clotting disorders. CONCLUSIONS: Normal tooth extractions are underestimated for their risk for postoperative bleeding, especially in the molar region. Anticoagulant therapy or congenital blood disorders present oral surgeons with a further challenge. CLINICAL RELEVANCE: Performing surgery before midday allows surgeons managing postoperative bleeding themselves for a better patient satisfaction. Intensified information about correct postoperative behavior is crucial. Prolonged blood coagulation should intensify follow-up checks. Patients with congenital blood disorders and patients at high risk for bleeding with the need for substitution of platelets or clotting factors should receive inpatient care. More potent, local applicable coagulant agents are required for these patients.

Complications after free flap surgery: do we need a standardized classification of surgical complications?

Our main objective was to apply a standard classification to surgical complications after free flap surgery for reconstructions of the head and neck. We used the modified Clavien-Dindo classification in a cohort of 79 patients who were having reconstructions with jejunal free flaps simultaneously with resections of oral and oropharyngeal cancer. The most common minor complication was the need for a blood transfusion, and the most common major complication of a respiratory nature. The medical complications, and those at the recipient site and the donor site were 53/79 (67%), 44/79 (56%), and 9/79 (11%), respectively. The Clavien-Dindo classification is suitable and can easily be used to evaluate postoperative complications after free tissue transfer.

Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane.

BACKGROUND AND PURPOSE: Sulforaphane is a naturally occurring compound found in broccoli and other cruciferous vegetables. Recently it gained attention because of its antiproliferative properties in many cancer cell lines. The aim of this study was to investigate whether sulforaphane could act as a radiosensitizer in head and neck squamous cell carcinoma cell lines. MATERIALS AND METHODS: Four head and neck squamous cell carcinoma cell lines (i.e., (HNSCC) SCC9, SCC25, CAL27, and FADU) were treated with sulforaphane and subsequently irradiated. Then proliferation and clonogenic assays were performed. Apoptosis was detected by flow cytometry. Possible regulation of Akt and Mcl-1 was investigated by western blotting. RESULTS: Sulforaphane and radiation in combination leads to stronger inhibition of cell proliferation and of clonogenic survival than each treatment method alone. Western blot analysis of Akt and Mcl-1 showed no changed expression. CONCLUSION: Sulforaphane is a promising agent in the treatment of head and neck cancer due to its antiproliferative and radio-sensitizing properties. A combination of sulforaphane and radiation decreases clonogenic survival. Apoptosis is not regulated through Akt or the Mcl-1 protein.

Functional imaging in head and neck squamous cell carcinoma: correlation of PET/CT and diffusion-weighted imaging at 3 Tesla.

PURPOSE: The purposes of this study were: (a) to prospectively assess the correlation between apparent diffusion coefficient (ADC) values and maximum standardized uptake values (SUVmax) in patients with head and neck squamous cell carcinomas (SCC); and (b) to assess ADC and SUVmax values in relation to different tumour grades and stages in our patient population. METHODS: The study group comprised 31 consecutive patients with biopsy-proven head and neck squamous cell carcinoma who were examined using a 3T MRI scanner with a 16-channel head and neck coil. In addition to routine sequences, axial (DWIBS) and sagittal (DW-EPI) diffusion-weighted sequences were obtained using b-values of 0 mm(2)/s and 800 mm(2)/s. The ADC maps were calculated automatically. The ADC values of the tumours were measured with three regions of interest (ROIs) of standard size, and an ROI covering the entire tumour. In all patients, contrast-enhanced, whole-body (18)F-FDG PET/CT was performed within 2 weeks of the MRI examination. SUVmax was measured for every tumour using a 3-D freehand ROI that covered the entire tumour. Two-way repeated measures ANOVA was used for group comparisons. The Spearman rank correlation test was performed for ADC values. RESULTS: Mean ADC values in the 31 SCC were 0.902 (± 0.134) with a ROI of standard size, and 0.928 (± 0.160) with the large ROI measurements on the axial DWIBS sequence. The ADC values of the tumours were significantly higher when measured with the sagittal DW-EPI sequence: 1.051 (± 0.211) and 1.082 (± 0.208). We observed no significant differences in ADC values and SUVmax between the various T stages or histological grades of the tumours. SUVmax values (26.5 ± 12) did not correlate with ADC values on DWIBS or EPI. CONCLUSION: There is no correlation between the FDG uptake and the ADC value in head and neck SCC. The three different tumour grades and four tumour stages present in our study population could not be differentiated based on ADC values or SUV.

Betulinic acid a radiosensitizer in head and neck squamous cell carcinoma cell lines.

BACKGROUND AND PURPOSE: Betulinic acid, a pentacyclic triterpene, is a new cytotoxic compound active on melanoma, neuroblastoma, glioblastoma and head and neck squamous cell carcinoma (HNSCC) cells. In combination with irradiation it has been shown to have an additive effect on growth inhibition in melanoma cells. In this study, the radiosensitizing effect of betulinic acid on sequential irradiation was investigated in HNSCC cell lines. MATERIAL AND METHODS: Two HNSCC cell lines, SCC9 and SCC25, were treated with increasing doses of betulinic acid and sequentially irradiated with a single boost of 4 Gy from a conventional radiation source. The cells were counted, the surviving fraction was determined, and colony-forming assays were performed. RESULTS: It could be shown that betulinic acid alone inhibits cell survival, affects cell survival additively in combination with irradiation and decreases clonogenic survival in both cell lines when applied alone. CONCLUSION: Betulinic acid could be a promising treatment agent in radioresistant head and neck cancer. A combination of betulinic acid with radiotherapy seems to be beneficial.

The cyclooxygenase-2 inhibitor nimesulide, a nonsteroidal analgesic, decreases the effect of radiation therapy in head-and-neck cancer cells.

BACKGROUND: No data are available on the effects of the cyclooxygenase-2 (COX-2) inhibitor nimesulide in combination with irradiation on the survival of head-and-neck carcinoma cells. MATERIAL AND METHODS: Two head-and-neck carcinoma cell lines (SCC9 and SCC25) were treated with nimesulide (50-600 microM) and irradiated concomitantly or sequentially. Early effects on cell survival were investigated by counting cell numbers, long-term effects by colony-forming assays. Cell-cycle effects were analyzed 24-72 h after treatment with nimesulide by flow cytometry. RESULTS: Unexpectedly, nimesulide solely inhibited cell proliferation without affecting colony-forming ability. In addition, no evidence for a radiosensitizing effect of nimesulide in short-term assays was seen. Nimesulide alone had no effect on clonogenic survival alone or in combination with radiation. CONCLUSION: Nimesulide differentially affects cell proliferation and clonogenic survival and may decrease the efficacy of radiotherapy. Short-term assays to assess tumor growth may not correctly predict the clinically relevant long-term effect of COX-2 inhibitors.

Inhibition of cytotoxicity of cisplatin by cyclooxygenase-2 inhibitor nimesulide in head and neck cancer cell lines.

Although head and neck cancer is a common malignancy, investigations have not yet improved the poor prognosis of patients. Therefore, it is important to find new cancer treatment modalities. Recent studies showed that cyclooxygenase, especially its isoform cyclooxygenase-2, is involved in tumorigenesis, tumor growth and metastasis. Inhibition of this enzyme by cyclooxygenase inhibitors has been shown to be antiproliferative in numerous cancer cell lines. The aim of this study was to investigate if the selective cyclooxygenase-2 inhibitor nimesulide could enhance cytotoxicity of the standard chemotherapeutic agent cisplatin. Head and neck squamous cell cancer cells were incubated with nimesulide and/or cisplatin, and counted after 24, 48 and 72 h treatment. Visualization of apoptotic cells was done by immunohistochemistry. We demonstrated that nimesulide inhibits the cytotoxic effect of cisplatin in HNSCC cells. Therefore, COX-2 inhibitor nimesulide may not be a good partner for cisplatin in combination therapy for cancer.

The effect of nimesulide, a selective cyclooxygenase-2 inhibitor, on Ets-1 and Ets-2 expression in head and neck cancer cell lines.

BACKGROUND: The protooncogenes Ets-1 and Ets-2 are involved in carcinogenesis of different tumors. Nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, has antiproliferative effects on tumor cells. The question arises whether nimesulide influences Ets-1 and Ets-2 synthesis in head and neck tumors. METHODS: Expression of Ets-1 and Ets-2 was analyzed in tumor tissues by immunohistochemistry. The influence of nimesulide and an extracellular signal-regulated kinase (ERK) inhibitor on cell proliferation of two head and neck cancer cell lines and Ets-1 and Ets-2 expression was determined by automated cell counting and Western blotting, respectively. RESULTS: Immunohistochemistry showed a high expression of Ets-1 and Ets-2 in tumor tissues. In both cell lines, Ets-1 and Ets-2 expression were reduced after 24 and 48 hours by nimesulide. CONCLUSION: Both Ets-1 and Ets-2 are overexpressed in head and neck cancer specimens. Inhibition of Ets-1 and Ets-2 expression in head and neck cancer cell lines by nimesulide might explain the proapoptotic property of this COX-2 inhibitor.

Combination of betulinic acid with cisplatin--different cytotoxic effects in two head and neck cancer cell lines.

Betulinic acid (BetA), a new experimental cytotoxic compound that is active against human melanoma cells and neuroectodermal tumor cells, has recently been shown to be also effective against head and neck squamous carcinoma cells (HNSCC). In this study we investigated BetA in combination with cisplatin in squamous cell carcinoma cell lines of the tongue. SCC25 and SCC9 were treated with BetA and/or cisplatin. Cells were counted with an automated analyzing system. Caspase activation was determined using the M30 Cyto-Death ELISA, expression of the anti-apoptotic protein Mcl-1 by Western blot analysis. Visualization of apoptotic cells was achieved by immunohistochemistry. Synergistic cytotoxic effect and the induction of apoptosis under combined treatment was observed in SCC25 cells only after 24 or 48 h, whereas treatment of SCC25 cells for 72 h with BetA and cisplatin showed antagonism or subadditive effects. In SCC9 cells, antagonism occurred over an increase of dose and time during treatment. Furthermore, we could not demonstrate a significant alteration in the expression of the anti-apoptotic protein, Mcl-1. Our in vitro data demonstrate that BetA seems to be an unlikely candidate for combination with cisplatin in the treatment of head and neck cancer.