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Purpose: Several observational studies in head and neck cancer have reported that allogenic blood transfusion is associated with increased postoperative complications, increased risk of tumor recurrence, and worse prognosis. The aim of this study was to identify preoperative and intraoperative factors predicting blood transfusion in patients undergoing surgery for oral and oropharyngeal cancer., Patients and Methods: We conducted a retrospective cohort study of patients undergoing tumor resection and free flap reconstruction for locally advanced oral and oropharyngeal squamous cell carcinoma between 2000 and 2008. The primary outcome variable was perioperative exposure to allogenic blood transfusion. Univariate and multivariate logistic regression models were used to determine predictors of blood transfusion., Results: A cohort of 142 participants was found eligible. In a multivariate model, Charlson score ≥ 1 (OR, 5.2; 95% CI, 1.4 to 19.3; P = .01), preoperative hemoglobin levels ≤ 12 g/dl (OR, 4.4; 95% CI, 1.2 to 16.2; P = .03), bone resection (OR, 5.1; 95% CI, 1.5 to 17.8; P = .01), and osseous free tissue transfer (OR, 8.8; 95% CI, 1.0 to 74.8; P = .046) were independently associated with an increased risk of blood transfusion., Conclusion: Our study identified patient- and surgery-related factors predicting a higher risk of exposure to allogenic blood transfusion. This readily available preoperative information could be used to better stratify patients according to their transfusion risk and may thereby guide blood conservation strategies in high-risk patients., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the impact of expression of epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition factor (c-Met), and insulin-like growth factor receptor 1 (IGF-1R) protein on response to treatment and survival in patients with oral and oropharyngeal squamous cell carcinoma (SCC). EGFR, c-Met, and IGF-1R immunohistochemical (IHC) scores were generated based on the incidence and intensity of expression of the biomarkers evaluated in paraffin-embedded sections of biopsy specimens taken before treatment from 113 patients given neoadjuvant chemoradiotherapy followed by resection for primary locally advanced oral and oropharyngeal SCC. Correlations were assessed between the IHC of the biomarkers and the patients' clinicopathological variables using Spearman's rank test. Cox's regression models were used to evaluate the impact of EGFR, c-Met, and IGF-1R, expression on survival. Almost all the patients showed expression of EGFR, c-Met, and IGF-1R (99%, 100%, and 100%, respectively). None of the biomarkers examined predicted response to neoadjuvant chemoradiotherapy or were associated with survival. In multivariate analysis, age (p=0.05), alcohol consumption (p=0.03), and pathological size/extent of the primary tumour after neoadjuvant treatment (ypT) status (p=0.009) were significantly associated with recurrence-free survival. Age (p=0.02) and alcohol consumption (p=0.02) were independently associated with overall survival. Although none of the biomarkers evaluated could be used as prognostic indicators, their common expression suggested a strong rationale for targeting EGFR, c-Met, and IGF-1R in the treatment of oral and oropharyngeal SCC., (Copyright © 2012 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate the postoperative platelet count changes in patients with oral and oropharyngeal squamous cell carcinoma undergoing preoperative chemoradiotherapy in order to test the hypothesis that the failure of platelets to recover to normal range within 7 days after surgery represents a significant risk factor for poor survival., Materials and Methods: A cohort of 102 patients with primary locally advanced oral and oropharyngeal squamous cell carcinoma undergoing neoadjuvant chemoradiotherapy and surgery was retrospectively analyzed. For each patient, platelet counts were evaluated prior to neoadjuvant treatment, prior to surgery and throughout postoperative days 1 to 7. The Kaplan-Meier method and Cox regression models were used to assess the impact of platelet count changes on survival., Results: Overall survival rate at 5 years was 28% for patients whose platelets did not recover by day 7, with 52% for patients whose platelets remained within a normal level or recovered to this by day 7 (p = 0.005). In multivariate analysis, failure of platelet recovery by day 7 was independently associated with shorter overall survival (p = 0.03)., Conclusions: We demonstrated that the failure of platelets to recover to normal range by the seventh postoperative day is an independent adverse prognostic factor in patients with oral and oropharyngeal cancer undergoing neoadjuvant treatment and surgery., Clinical Relevance: Our results indicate that physicians should pay closer attention to monitoring the postoperative platelet count course, as it may predict the clinical outcome of patients with oral and oropharyngeal cancer.

Objective: The hepatocellular carcinoma-related protein 1 (HCRP1) is a key factor in the degradation of the epidermal growth factor receptor. In this study, we assessed the prognostic significance of HCRP1 expression in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC)., Methods: HCRP1 expression was determined by immunohistochemistry on tissue biopsy sections of 111 patients with locally advanced OOSCC undergoing neoadjuvant chemoradiotherapy followed by surgery. The Kaplan-Meier method and Cox regression models were used for survival analyses., Results: Low HCRP1 expression was associated with poor recurrence-free survival (P = 0.046) and overall survival (P = 0.03). Multivariate analysis revealed that low HCRP1 expression remained an independent risk factor for relapse (HR 2.98, 95% CI 1.19-7.49, P = 0.02) and death (HR 3.04, 95% CI 1.19-7.79, P = 0.02)., Conclusion: Low HCRP1 expression was found to be of adverse prognostic significance in patients with OOSCC who received preoperative chemoradiotherapy., (© 2012 John Wiley & Sons A/S.)

Objectives: Treatment outcome of patients with oral and oropharyngeal squamous cell carcinoma (OOSCC) achieving complete pathologic response at the primary site (ypT0) but incomplete response in loco-regional lymph nodes after preoperative chemoradiation (ypN+) is poorly described in the literature. This study's objective was to assess the survival of patients with OOSCC with ypT0N+ disease., Study Design: 176 patients with primary locally advanced OOSCC undergoing preoperative chemoradiotherapy were stratified according to the pathologic TNM classification into 6 groups: ypT0N0M0 (46%), ypT0N+M0 (10%), ypTNM I (24%), ypTNM II (4%), ypTNM III (6%), and ypTNM IV (10%)., Results: Three-year overall survival (OS) and recurrence-free survival (RFS) rates for the ypT0N+M0 group were both 61.8% and were similar to those of the ypTNM I group (OS 62.4%; RFS rate of 59.2%)., Conclusions: Survival analyses showed that patients with OOSCC with ypT0N+ disease have a similar prognosis to those with pathologic TNM stage I., (Copyright © 2013 Elsevier Inc. All rights reserved.)

With growing evidence on the role of inflammation in carcinogenesis, the presence of a systemic inflammatory response has been proposed as having prognostic significance in a wide range of cancers. The aim of the study was to assess the value of pretreatment neutrophil-to-lymphocyte ratio (NLR) in predicting disease-specific survival (DSS) in patients with oral cancer undergoing preoperative chemoradiotherapy. A cohort of 97 patients with locally advanced oral squamous cell carcinoma receiving preoperative chemoradiotherapy was retrospectively examined. The impact of NLR and other potential prognostic factors on DSS was assessed with the Kaplan-Meier method and multivariate Cox regression analysis. Sixty-nine patients had a high pretreatment NLR, with NLR > 1.9 considered as high according to receiver operating characteristic curve analysis. In univariate analysis, high pretreatment NLR (p = 0.018), positive perineural invasion (p < 0.001) and advanced pathologic TNM stage after neoadjuvant therapy (p < 0.001) were predictive of shorter DSS. In multivariate analysis, advanced pathologic TNM stage after neoadjuvant therapy (HR 1.71, 95 % CI 1.17-2.48, p = 0.005), positive perineural invasion (HR 3.67, 95 % CI 1.11-12.13, p = 0.033) and high pretreatment NLR (HR 10.37, 95 % CI 1.28-84.08, p = 0.029) remained independently associated with poor DSS. A high pretreatment NLR is a significant independent predictor of shorter DSS in patients with oral cancer receiving preoperative chemoradiotherapy.

Evidence indicates that allogenic packed red blood cell transfusion results in the host's immunomodulation, and is associated with adverse clinical outcomes after surgery. The aim of this study was to test whether allogenic leukocyte-depleted blood transfusion represents a significant risk factor for postoperative morbidity after oral and oropharyngeal cancer surgery. A total of 142 patients, diagnosed for the first time with oral and oropharyngeal squamous cell carcinoma, and receiving neoadjuvant chemoradiotherapy followed by surgery between 2000 and 2008 were retrospectively included in this study. Univariate and multivariate logistic regression models were calculated to identify predictors of postoperative complications. We found a significantly higher complication rate in the group of transfused patients compared to patients not exposed to transfusion (complication rate of 84% and 39%, respectively, p<0.001). On multivariate analysis, the amount of packed red blood cells transfused (for 1-4 units transfused: adjusted OR, 2.59; 95% CI, 1.24-5.39; p=0.011; for more than >4 units transfused: adjusted OR, 5.29; 95% CI, 2.01-13.88; p=0.001) and Charlson's comorbidity score ≥1 (adjusted OR, 2.81; 95% CI, 1.38-5.70; p<0.004) were independently associated with the development of postoperative complications. Allogenic leukocyte-depleted blood transfusion is independently associated with increased postoperative complications in patients undergoing surgery for oral and oropharyngeal cancer. This association follows a dose-response relationship, as patients who received larger amounts of packed red blood cells showed a significant trend toward higher postoperative morbidity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2011 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to evaluate whether the immunohistochemical expression of p53, p21, p27, cyclin D1, and Ki67 can predict therapy response and survival in patients with oral and oropharyngeal squamous cell carcinoma treated with preoperative chemoradiation., Methods: Biomarker expression was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded pretreatment biopsies of 111 homogenously treated patients. We assessed the association between clinicopathological variables including response to neoadjuvant chemoradiotherapy as well as the survival of the patients and the expression of the biomarkers as both dichotomized (positive vs. negative) and continuous variables., Results: Biomarker overexpression on the basis of pre-selected cutoff points was seen in 66 of 111 (59%) cases for p53, in 77 (69%) for p21, in 48 (43%) for p27, in 81 (73%) for cyclin D1, and in 54 (49%) cases for Ki67, respectively. None of the examined biomarkers was able to predict response to neoadjuvant chemoradiotherapy or was associated with survival outcome. Post-treatment pathologic TNM stage (P < 0.001), pathologic response (P < 0.001), and perineural invasion (P < 0.001) were the only factors having a significant effect on recurrence-free survival. Post-treatment pathologic N stage (P = 0.005), post-treatment pathologic TNM stage (P < 0.001), pathologic response (P < 0.001), and perineural invasion (P = 0.001) had a significant impact on overall survival., Conclusions: Our results suggest that the biomarkers p53, p21, p27, cyclin D1, and Ki67 have no impact on treatment response and survival in patients with oral and oropharyngeal cancer treated with preoperative chemoradiation., (© 2011 John Wiley & Sons A/S.)

Introduction: The aim of this study was to review survival and locoregional control in patients with advanced oral and oropharyngeal squamous cell carcinoma treated by multimodal therapy with preoperative radiochemotherapy and radical surgery., Material: Retrospective cohort study., Methods: Included in this analysis are 276 consecutive patients with UICC disease stages III and IV (T2: 13.0%; T3: 16.7%; T4: 70.3%; N0: 29.7%; N1: 20.3%; N2: 45.3%; N3: 4.7%; stage III: 16.3%; stage IV: 83.7%). All patients received preoperative radiochemotherapy (50Gy, Mitomycin and 5-Fluorouracil) and radical locoregional resection., Results: Median surveillance period was 101.4 months (24-202 months). 5-year overall survival probability was 53.9%. 5-year local control probability was 70.2%., Conclusion: These results underline the reliability of preoperative treatment of patients with oral and oropharyngeal cancer.

Purpose: To analyze mortality and causes of death in patients who received preoperative radiochemotherapy and underwent radical surgery for advanced oral or oropharyngeal cancer., Patients and Methods: A total of 222 patients who underwent multimodality treatment from 1990 to 2000 were included in the study. The inclusion criterion was International Union Against Cancer (UICC) disease stage II to IV (T2, 33.3%; T3, 12.6%; T4, 54.1%). Patients received preoperative radiotherapy 50 Gy and concomitant chemotherapy with mitomycin and 5-fluorouracil. Radical local-regional en bloc resection was performed in all patients. Survival status and causes of death were ascertained from the National Health Registry. Death certificates and autopsy reports were consulted when hospital files failed to provide reliable data., Results: After a median surveillance period of 72.3 months (range, 24 to 152 months), 59% of patients were alive, 21% had died of recurrence, 5% had died perioperatively, and 15% had died from other causes. Of these, a second cancer in the head and neck region or the lower respiratory tract or the upper digestive tract was found in 7.3%. Although 93% of deaths related to recurrent disease occurred within the first 36 months after surgery, the remaining causes of death did not reveal a specific temporal pattern., Conclusion: Favorable survival data were registered for patients with advanced squamous cell carcinoma of the oral cavity who underwent combined treatment protocols. These patients frequently die of comorbidities. Because recurrent disease is a less common cause of mortality than are other causes, the latter should receive attention during surveillance.

Objective: The aim of this study was to analyze long-term implant survival in the mandible after radiotherapy and radical surgery in oral cancer patients., Study Design: Between 1990 and 2003, 71 patients (15 females, 56 males; average age 57.8 years, range 16-84.1 years) were treated with dental implants after radiochemotherapy and ablative surgery of oral cancer. Radiation therapy was delivered in daily fractions of 2 Gy given on 25 days (total dose of 50 Gy). Oral defects were reconstructed microsurgically with jejunal, iliac crest or radial forearm grafts. Thereafter 316 dental implants were placed in the non-irradiated residual bone (84; 27%), irradiated residual bone (154; 49%) or grafted bone (78; 25%) at various intervals (mean interval 1.41 (+/- 1.01) years, range 0.34-6.35 years)., Results: The mean follow-up time after implant insertion was 5.42 (+/- 3.21) years (range 0.3-13.61 years). The overall 2-, 3-, 5-, and 8-year survival rates of all implants were 95%, 94%, 91% and 75%. Forty-four implants were lost in 21 patients during the observation period. Irradiation of the mandibular bone showed significantly (P = 0.0028) lower implant survival compared with non-irradiated mandibular bone. The 8-year survival rate in the non-irradiated residual bone (two loss), irradiated residual bone (29 loss) or grafted bone (13 loss) were 95%, 72% and 54%, respectively. Time of implantation after irradiation showed no statistically significant influence. Implant brand, length or diameter or the incidence of resective surgery on the mandible and gender of patients had no statistically significant influence on implant survival., Conclusion: Radiation therapy with 50 Gy was significantly related to shorter implant survival in mandibular bone. Survival was lowest in grafted bone. Time of implant placement had no statistically significant influence on survival under the conditions of this study. Although implant survival is lower in irradiated mandibles, implants significantly facilitate prosthodontic treatment and enhance outcome of oral rehabilitation in cancer patients.

This study examined free flap reconstruction of surgical defects of the oral cavity and oropharynx after preoperative radiochemotherapy. Included in this analysis are 303 prospectively followed patients who underwent a multimodal treatment regime for advanced oral and oropharyngeal carcinoma. All patients received preoperative radiochemotherapy (Mitomycin C, 5-FU, 50 Gy), ablative surgery, and primary free flap reconstruction. Patient characteristics, surgical parameters like duration of surgery and ischaemia, size of defect, type of transplant, and clinical outcome parameters like duration of intensive care and hospitalization, type of complications, necessity and type of revision surgery were statistically evaluated. Overall flap success rate was 93.1%. Sixty seven patients required revision and 21 flaps (6.9%) were lost. Overall complication rate was 22.1%. Mean duration of intensive care (DOIC) and duration of overall postoperative hospitalization (DOH) were 11.0+/-9.6 days and 35.9+/-26.3 days, respectively. Flap success and flap related complications after 50 Gy focal radiation dosage were found in a comparable range as in published series of reconstructions in uncompromised tissue.

The purpose of this study was to assess the prognostic value of histological response to preoperative radiochemotherapy in an established multimodal therapy concept for advanced oral and oropharyngeal cancer. Two hundred and twenty-two patients who underwent preoperative radiochemotherapy (RCT: 50 Gy, mitomycin C and fluorouracil) and radical surgery were retrospectively evaluated. Resected tumours of all patients were histologically analysed and response to RCT was classified in histopathological grades of regression (RG). In a multivariate statistical analysis, RG was compared with established factors regarding their predictive value for overall and disease-specific survival. The 5-year overall survival probability in the different groups of histopathological regression grades were: RG1 (no vital tumour): 73.4%, RG2 (minimal tumour remnants encompassing less than 5%): 72.1%, RG3 (5-50% vital tumour cells): 41.9%, RG4 (more than 50% vital tumour): 37.9%. For disease-specific survival probability no significant differences were found between both groups of "responders" (RG1 and RG2) nor between "non-responders" (RG3 and RG4), whereas responders and non-responders differed significantly from each other (log-rank test; p < 0.001). T-classification, N-classification and disease stage, histological grading, tumour site, age, and sex had less prognostic value than RG in a Cox regression model. In the neoadjuvant multimodal therapy concept, histological response to preoperative RCT is a crucial prognostic factor even when surgical R0-resection is accomplished. Thus, non-responders have to be regarded as high-risk patients for recurrence and may benefit from further therapy.

To analyse survival and locoregional control in patients with advanced oral and oropharyngeal squamous cell carcinoma (SCC) after multimodal therapy with preoperative radiochemotherapy (RCT) and radical surgery. We included in this analysis 222 patients who underwent multimodal therapy between 1990 and 2000. Eligible were patients with UICC disease stages II-IV (T2: 33.3%; T3: 12.6%; T4: 54.1%; N0: 45.9%; N1: 17.6%; N2: 33.3%; N3: 3.2%; stage II: 21.1%; stage III: 14.9%; stage IV: 64%). Patients received preoperative radiochemotherapy consisting of Mitomycin C (15-20 mg/m2, day 1) plus 5-Fluorouracil (750 mg/m2/24 h-infusion, days 1-5) and concomitant radiotherapy for a total dose of 50 Gy. Radical locoregional en bloc-resection according to the pretherapeutic tumour extension was carried out in all patients. After a median surveillance period of 72.3 months (24-152 months), 131 patients (59%) were alive, and 91 (41%) patients died; 12 (5%) of them died postoperatively, 46 (21%) due to tumour recurrence, and 33 (15%) deaths were not directly related to the primary tumour. Overall survival probability was 76% after 2 years, and 62% after 5 years. Two- and 5-year local control probability were 88 and 81%, respectively. Regarding the high percentage of stage IV disease in the reported patients, the multimodal concept is an effective therapy offering excellent survival and local control probability.

Human tumor cells from 22 patients with squamous cell carcinomas of the oral cavity were cultivated in vitro and then subjected to sensitivity tests to cytotoxic drugs such as methotrexate, 5-fluorouracil, cisplatin and bleomycin. Tumor cell proliferation showed drug-specific reaction patterns and time-dose-dependent variations. While the effect of methotrexate on cell proliferation was insignificant, 5-fluorouracil caused a growth suppression of 50%. Cisplatin and bleomycin suppressed cell growth by more than 90%.

Lactate dehydrogenase (LDH; EC 1.1.1.27) isoenzymes in human epithelial cells from squamous cell carcinomas and healthy tissues of the oral cavity of five patients were analyzed using isoelectric focussing. A new basic isoenzyme and high LDH-7 and LDH-9 activity were found in tumor cells in contrast to epithelial cells of adjoining nontumor tissue. These findings indicate that gradual changes in the percentage distribution of LDH isoenzymes may represent a useful parameter of disease activity in patients with squamous cell carcinomas.

In 60 patients with primary squamous cell carcinomas of the oral cavity, clinical examination was complemented by 5 additional diagnostic procedures prior to surgery to assess tumor extension. Comparing these finding with the histological evaluation of the excised tissue demonstrated that, while the TNM classification remains the foundation of all tumor diagnostic procedures, the use of radiography, bone scintigraphy and CT is indispensable to ascertain the amount of tissue to be excised. CT competes with B-scan sonography in cervical lymph node diagnostics. Tumor scintigraphy has been found to be an unreliable method.

Human epithelial cells and fibroblasts from malignant tumors and healthy tissues of the oral cavity were exposed in vitro to increasing concentrations of 5-fluorouracil. In order to determine whether the two cell types showed a difference in uptake, accumulation was measured over time using tritiated fluorouracil. Maximal drug uptake occurred in highly proliferative epithelial cells from cancerous tissue at 3 h, whereas fibroblasts from the same tissue and other cell types from healthy tissue exhibited a steadily increasing uptake over a long period of time. By use of [3H]methionine, a direct correlation could be demonstrated between the amount of incorporated drug and the fall in the rate of de novo protein synthesis. Furthermore, suppression of protein synthesis was closely related to the inhibition of cell division. These results indicate that the level of de novo protein synthesis can be a direct measure of the anticancer effect of fluorouracil.

Vestibuloplasty together with a loosening of the tongue and covering the mucosal defects either with a split thickness skin graft or an autologous mucosal graft was performed on 35 patients previously treated for squamous cell carcinoma. The interval between tumor resection and the reconstructive procedures averaged 20 months. In 34 patients the denture bearing area improved, and in 31 patients, better mobility of the tongue occurred with, therefore, better phonation.