Oral Oncology - Articles in Press

Therapy options and long-term results of sinonasal malignancies - Corrected Proof

2012-05-18

Summary: Objectives: Nasal and paranasal sinus malignancies are rare. The most common lesions are located in the nasal cavity and the maxillary sinus, although they also occur in the ethmoid, sphenoid and frontal sinuses. Treatment often combines surgery, radiotherapy and chemotherapy. Endoscopic surgical approaches are increasingly used in order to reduce the morbidity associated with standard open resection. The aim of our study was to analyse the long-term treatment results of sinonasal malignancies (SNM), with a special focus on surgical approaches.Materials and Methods: A retrospective review of 123 patients treated in a tertiary referral centre from 1992 to 2008 was conducted, which included information on tumour stage, histology, treatment and follow-up.Results: A variety of histological types were found with squamous cell carcinoma being the most frequent (n=38), followed by melanoma (n=24) and adenocarcinoma (n=21). Open surgery was performed in 55 patients, and endoscopic resection was performed in 28 patients. Nineteen patients were treated with primary radiation therapy (RTX), four underwent primary chemotherapy (CTX), and 15 had primary chemoradiation (RCTX). Two patients died prior to therapy onset. A comparison of survival rates did not show a significant difference between the treatment groups. Patients that underwent endoscopic resection had significantly fewer postoperative complications.Conclusion: In carefully selected patients, endoscopic surgery of SNM showed a similar outcome as open surgery, but with a significantly lower complication rate.

New rehabilitation protocol for oral sinus communications in BRONJ patients - Corrected Proof

2012-05-17

The management of bisphosphonate-related osteonecrosis jaw (BRONJ) is challenging because most surgical and medical interventions may not eradicate it. More alarming is performing prosthetic rehabilitation of these patients, subject not enough discussed in the literature. The demand of BRONJ patients in need of prosthetic rehabilitation has being dramatically increased in Brazil. We believe that this is also a huge problem in others countries too. The professionals are concerned about the possible induction of new lesions due to trauma caused by the fabrication and use of prostheses. However, the oral rehabilitation of BRONJ patients is of paramount importance for their quality of life. For circumvent this problem our research group in the School of Dentistry of the University of São Paulo developed a new protocol for obtaining prosthesis with chemical and mechanical characteristics conferring an atraumatic and atoxic pattern (). After more than 4years of follow-up there is no recurrence of the BRONJ lesions. There is a lack of information on the use of osseointegrated implants in these patients, thus, due to the long half-life of BFs in the patients, or because patient will be still using BFs, new BRONJ lesions can occur, particularly in areas subject to trauma, our group opted for a denture fabrication based on those indicated for patients irradiated for head and neck cancer. Several parameters were considered for the construction of such prosthesis, including resin type, polymerization cycle, prosthesis finishing and internal adaptation, as described in the chart below. We believe that oral health professionals and their BRONJ patients worldwide will be beneficiated with this prosthetic rehabilitation protocol. We hope to have more discussion about this subject for now on.

A randomized trial of induction chemotherapy plus concurrent chemoradiotherapy versus induction chemotherapy plus radiotherapy for locoregionally advanced nasopharyngeal carcinoma - Corrected Proof

2012-05-16

Summary: The aim of this randomized study was to compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) for patients with locoregionally advanced nasopharyngeal carcinoma. From August 2002 to April 2005, 408 patients were randomly divided into two groups: an IC+CCRT group and an IC+RT group. Patients in both groups received the same induction chemotherapy: two cycles of floxuridine (FuDR)+carboplatin (FuDR, 750mg/m2, d1-5; carboplatin, area under the curve [AUC]=6). The patients received radiotherapy 1week after they finished the induction chemotherapy. The patients in the IC+CCRT group also received carboplatin (AUC=6) on days 7, 28, and 49 of radiotherapy. Eight patients did not meet the inclusion criteria, and the remaining 400 cases were analyzed. Grade III or IV toxicity was found in 28.4% of the patients in the IC+CCRT group and 13.1% of those in the IC+RT group (P<.001). Five-year overall survival rates were 70.3% and 71.7% (P=0.734) in the IC+CCRT and IC+RT groups, respectively. No significant differences in failure-free survival, locoregional control, and distant control were found between the two groups. Compared with the IC+RT program, the IC+CCRT program used in the present study did not improve the overall survival and failure-free survival in patients with locoregionally advanced nasopharyngeal carcinoma. Using carboplatin in the concurrent chemoradiotherapy was not suitable for nasopharyngeal carcinoma.

Highly-conformal intensity-modulated radiotherapy reduced toxicity without jeopardizing outcome in patients with paranasal sinus cancer treated by surgery and radiotherapy or (chemo)radiation - Corrected Proof

2012-05-14

Summary: Objectives: To report oncologic outcomes of patients with paranasal sinus cancer (PNSC) treated by surgery and radiotherapy or (chemo)radiation and to investigate the impact of improving the radiation technique on outcomes and toxicity.Materials and Methods: Between 1999 and 2010, 82 consecutive patients with PNSC were treated by surgery and radiotherapy or by definitive (chemo)radiation. Three-dimensional conformal (3DCRT) or highly-conformal intensity-modulated RT (IMRT) was used. Endpoints were local control (LC), regional control (RC), disease-free (DFS), cause-specific (CSS), and overall survival (OS), late toxicity, and quality-of-life (QoL).Results: After median follow-up of 51months, the 5-year actuarial rates of LC, RC, DFS, CSS, and OS were 74%, 94%, 56%, 64%, and 54%, respectively. Grade ⩾2 late toxicity at 5-years was 28%. High T-stage and perineural invasion were significantly associated with poor LC and RT-technique with late toxicity. Late toxicity was significantly lowered using IMRT, compared to 3DCRT (17% vs. 52%, p<0.0001). Visual preservation were significantly improved using IMRT (88% and 65%, respectively, p=0.01). LC-rate was also improved by IMRT (80% vs. 64%, respectively, p=0.2). QoL-scores deteriorated during and shortly after treatment but returned in almost all scales to baseline levels within 3–12months.Conclusions: Surgery and radiotherapy or definitive (chemo)radiation resulted in good LC rates but with high rate of late side-effects. However, late toxicity and permanent visual impairment were significantly decreased by using highly-conformal IMRT without jeopardizing outcome. The improvements in the therapeutic ratio achieved by using IMRT would allow dose escalation of RT to further improve outcomes.

The clinical determinants of malignant transformation in oral epithelial dysplasia - Corrected Proof

2012-05-14

Summary: Background: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED).Methods: We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade.Results: Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5years, with significant predictors being: non-smoking status (χ2=15.1, p=0.001), site (χ2=15.3, p=0.002), non-homogeneous appearance (χ2=8.2, p=0.004), size of lesion >200mm2 (χ2=4.7, p=0.03) and, of borderline significance, high grade (χ2=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation.Conclusions: Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation.

Erratum to “Management of dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck receiving cetuximab and radiotherapy” [Oral Oncol 48 (4) (2012) 293–297] - Corrected Proof

Luis Cabezón-Gutiérrez, Parham Khosravi-Shahi, Yolanda Escobar-Álvarez — 2012-05-14

The publisher regrets that the authors names were incorrect in the original article and should be as above. The publisher would like to apologise for any inconvenience caused.

Corrigendum to ‘Continuous intra-arterial infusion chemotherapy as a palliative treatment for oral squamous cell carcinoma in octogenarian or older patients’ [Oral Oncology 46/7 (2010) 559–563] - Corrected Proof

Chih-Fung Wu, Chih-Jen Huang, Kao-Ping Chang, Chun-Ming Chen — 2012-05-14

The authors regret there was a mistake in the date of institutional IRB approval in the above mentioned manuscript. The retrospective chart-review study (Oral Oncology 2010: 46; 559–563) was submitted to the IRB (Institutional Review Board) of KMUH (record: #KMUH-IRB-990204) on 06/23/2010 for review and then received the approval on 09/23/2010.

Expression of ERCC1 predicts clinical outcome in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy - Corrected Proof

Pei-Yu Huang, Yan Li, Hai-Qiang Mai, Rong-Zhen Luo, Yu-Chen Cai, Li Zhang — 2012-05-09

Summary: The aim of the present study was to evaluate the correlation between excision repair cross-complementation group 1 (ERCC1) protein with the clinical outcome of nasopharyngeal carcinoma (NPC) patients treated with cisplatin-based induction chemotherapy. One hundred one Stage III–IVB nonkeratinizing NPC patients who were treated with cisplatin (DDP)+fluorouracil (5-Fu) induction chemotherapy were recruited. Pre-treatment tumor biopsy specimens were analyzed for ERCC1 by immunohistochemistry. The relationship of ERCC1 expression and chemotherapy response and survival of these NPC patients was analyzed. The objective response to induction chemotherapy of NPC patients with low ERCC1 expression compared with high ERCC1 expression was 88.2% vs. 72% (P=0.041). The 5-year distant failure-free survival (D-FFS) of NPC patients with low ERCC1 expression compared with high ERCC1 expression was 73.5% vs. 51.3% (P=0.037). ERCC1 expression was a significant prognostic factor for overall survival and D-FFS using Cox regression analysis. High tumor ERCC1 expression predicts low chemotherapy response and poor survival mainly caused by more metastasis in locoregionally advanced NPC treated with cisplatin-based induction chemotherapy.

Preoperative vs. postoperative radiochemotherapy in patients with N2 squamous cell carcinoma of the oral cavity - Corrected Proof

2012-05-04

Summary: Background: The aim of our study was to evaluate retrospectively whether neoadjuvant or adjuvant radiochemotherapy yields better survival for patients with N2-oral squamous cell carcinoma and to identify subgroups, which may benefit from one of the therapeutic settings. No studies have been carried out to investigate whether radiochemotherapy should be applied before or after surgery.Methods: In total, 151 patients with oral squamous cell carcinoma with N2-nodal-status were reviewed. Eighty five patients received neoadjuvant radiochemotherapy, 66 patients were treated with surgery and adjuvant radiochemotherapy. Overall survival was plotted by Kaplan–Meier analysis. Prognostic factors were identified through univariate and multivariate analysis.Results: Patients treated with neoadjuvant radiochemotherapy had a significantly improved 5-year survival in comparison to patients, who received adjuvant radiochemotherapy (46.3% vs. 27.4%, p=0.035). A subgroup analysis by T-stage revealed that neoadjuvant and adjuvant radiochemotherapy yielded similar 5-year survival rates for patients with T2N2-tumors (42.3% vs. 41.2%, p=0.871), whereas patients with T4bN2-tumors significantly benefitted from neoadjuvant treatment (37.3% vs. 9.7%, p=0.019).Conclusions: Neoadjuvant radiochemotherapy is an effective treatment for patients with nodal status N2-oral squamous cell carcinoma, however prospective randomized trials are needed to confirm, which patients should be treated with neoadjuvant or adjuvant radiochemotherapy.

Dermatitis associated with cetuximab and radiotherapy: The potential benefit with recombinant human epidermal growth factor and a concern regarding the use of steroids - Corrected Proof

Swaroop Revannasiddaiah, Priyanka Thakur, Manish Gupta — 2012-04-25

With interest we read the review article titled ‘Management of dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck receiving cetuximab and radiotherapy’ by Gutierrez et al. published online on 2 December 2011 in Oral Oncology.

Effects of multidisciplinary care on the survival of patients with oral cavity cancer in Taiwan - Corrected Proof

2012-04-25

Summary: Objectives: The incidence of oral cavity cancer is high in Taiwan. To improve patient survival, multidisciplinary team (MDT) care was implemented. This research compared the survival of MDT care participants/non-participants and examined the effect of MDT care on patient characteristics.Materials and Methods: In this study, 19,513 patients with newly diagnosed oral cavity cancer were recruited from 2004 to 2007 in Taiwan. Matching based on the propensity of receiving MDT care was used. In total, 9297 patients were observed until 2008. A Cox proportional hazards model was applied to elucidate the relative risks of death.Results: The relative risk of death was lower for patients with MDT care than for those without such care (HR=0.84; 95% CI=0.78–0.90). Males had a higher risk of death than females (HR=1.20; 95%CI=1.04–1.38). Older age, lower income, and more severe comorbidity were associated with a higher risk of death. The effect of MDT care was stronger for older patients than for younger patients. Patients treated in public hospitals had a 1.24-fold (95%CI=1.13–1.36) higher risk of death than patients treated in private hospitals. Patients treated in hospitals or by attending physicians with higher service volumes had a lower relative risk of death (HR=0.89 and 0.78, respectively). The effect of MDT care was strong among patients with less severe comorbidities and patients without catastrophic illnesses.Conclusion: The relative risk of death was lower for MDT care participants. The effect of MDT care was stronger among older patients and patients with fewer comorbidities.

Oral cavity, pharyngeal and salivary gland cancer: Disparities in ethnicity-specific incidence among the London population - Corrected Proof

Chris D. Donaldson, Ruth H. Jack, Henrik Møller, Margreet Lüchtenborg — 2012-04-23

Summary: Objectives: We examined the association between ethnicity and the incidence of oral and pharyngeal cancers in the London population.Methods: Data on London residents diagnosed with oral and pharyngeal cancer (ICD-10 codes C00–C14) between 1998 and 2007 were retrieved from the Thames Cancer Registry. Age-standardised incidence rate ratios (IRR) for cancers of the nasopharynx (C11), oropharynx (C09–C10), hypopharynx (C12–C13), oral cavity (C00.3–C06), salivary glands (C07–C08) and Waldeyer’s ring (C02.4, C09, C11.1, C14.2) were calculated for different ethnic groups using White males and females as the baseline groups.Results: Records on 5833 individuals were examined, and ethnicity information was available for 4679 (80%) of these patients. The incidence rate of oral and pharyngeal cancer combined was 9.0 and 3.9 per 100,000 for males and females, respectively. Compared with their White counterparts, the highest incidence rate ratios of nasopharyngeal cancer were seen in Chinese males (IRR: 23, 95% confidence interval (CI): 7–73) and females (IRR: 16, 95% CI: 2–107). Waldeyer’s ring cancers were most common in Bangladeshi and White groups. Analysis of the oropharynx and oral cavity cancers gave rise to variable but less obvious patterns among the different ethnic groups, whereas less variation was observed between ethnic groups for cancers of the hypopharynx and salivary glands.Conclusion: The incidence rates of individual oral and pharyngeal cancer types are low, but seem to vary by ethnic group. The variation in incidence appears to be unique to the different cancer subtypes and may therefore reflect specific ethnicity-related risk factors.

Expression of podoplanin and ABCG2 in oral erythroplakia correlate with oral cancer development - Corrected Proof

2012-04-23

Summary: Oral erythroplakia (OE) is a notoriously aggressive oral premalignant lesion with a high tendency to oral cancer development, but it’s biological behavior is largely unknown. The objective of the current study was to determine podoplanin and ABCG2 immunoexpression in OE and both correlation to malignant transformation of OE. In a retrospective follow-up study, the expression patterns of podoplanin and ABCG2 were determined using immunohistochemistry in samples from 34 patients with OE, including patients with untransformed lesions (n=17) and patients with malignant transformed lesions (n=17).Podoplanin and ABCG2 expression was observed in 15 (44.1%) and 21 (61.8%) of 34 patients, respectively. Multivariate analysis revealed that podoplanin and ABCG2 expression was associated with 6.31-fold (95% confidence interval [CI], 1.02–38.92; P=0.047) and 14.39-fold (95% CI, 2.02–102.29; P=0.008) increased the risk of transformation, respectively. Point prevalence analysis revealed that 90.9% (95% CI, 70.7–100) of the patient with both podoplanin and ABCG2 positivity developed oral cancer. Collectively, our data indicated that the expression patterns of podoplanin and ABCG2 in OE were associated with oral cancer development, suggesting that podoplanin and ABCG2 may be valuable predictors for evaluating oral cancer risk.

Development of oral cancer screening test by detection of squamous cell carcinoma among exfoliated oral mucosal cells - Corrected Proof

Takuma Kugimoto, Kei-ichi Morita, Ken Omura — 2012-04-23

Summary: Objectives: The early detection of oral cancer improves patient outcomes. However, despite our growing knowledge of oral cancers, patients often present with advanced disease. The development of simple screening methods is desirable to provide an alternative to screening examinations by specialists. Thus, we developed a method of oral cancer detection among exfoliated oral mucosal cells, and we evaluated the feasibility of implementing an oral cancer screening test that is examiner independent.Material and methods: The study population consisted of 185 subjects: 89 with oral cancer, 18 with oral leukoplakia, and 78 controls. We used real-time polymerase chain reaction (PCR) to detect the biomarkers serpin peptidase inhibitor B3 (SCCA1), interleukin 15 (IL-15), and thrombomodulin (THBD).Results: The sensitivities for the detection of oral cancer and oral leukoplakia were 72.0% (77/107) with SCCA1, 75.7% (81/107) with IL-15, and 56.1% (60/107) with THBD, and the specificities were 73.1% (57/78) with SCCA1, 64.1% (50/78) with IL-15, and 78.2% (61/78) with THBD. Analysis of the sensitivity according to tumor size revealed that sensitivity was lower for large tumors. When analyzing the sensitivity according to the clinical growth pattern, the sensitivity was observed to be low for endophytic tumors.Conclusion: We developed an oral cancer screening test based on real-time PCR analysis of SCCA1 that is examiner independent, and the sensitivity and specificity were approximately 70%; therefore, we concluded that the performance of this method using a single biomarker was suboptimal.

The strength/weakness of the AJCC/UICC staging system (7th edition) for nasopharyngeal cancer and suggestions for future improvement - Corrected Proof

2012-04-23

Summary: Background and purpose: To evaluate the current AJCC/UICC staging system (7th edition) for nasopharyngeal carcinoma and to explore for future improvement.Materials and methods: A total of 985 patients, initially staged with preceding 5–6th edition, were retrospectively re-staged with the 7th edition. All were assessed by magnetic resonance imaging, and all 945 non-disseminated patients were irradiated with conformal/intensity-modulated technique.Results: Staging factors by both the 5–6th edition and the 7th edition were strongly significance for important endpoints (p<0.001). Down-staging of the previous T2a to T1 and, stages IIA to I in the 7th edition was appropriate. However, the impacts on overall stage distribution and prognostication were minimal. Further down-staging of the current T2 to T1, N2 to N1, stages II to I, and merging of N3a and N3b, stages IVA and IVB were suggested. With the 7th edition, the 5-year disease-specific survival (DSS) was 100% for stage I, 95% for II, 90% for III, 67% for IVA, 68% for IVB and 18% for IVC. The corresponding DSS for the proposed stages I, II, III and IV were 95%, 86%, 67% and 18%, respectively.Conclusions: The changes introduced in the 7th edition were appropriate, but the magnitude of improvement was minimal. With improving results by modern management, further simplification of the staging system is suggested. The proposed system could lead to more accurate prognostication, further validation is warranted.

A systematic review of head and neck cancer quality of life assessment instruments - Corrected Proof

2012-04-23

Summary: Although quality of life (QOL) is an important treatment outcome in head and neck cancer (HNC), cross-study comparisons have been hampered by the heterogeneity of measures used and the fact that reviews of HNC QOL instruments have not been comprehensive to date. We performed a systematic review of the published literature on HNC QOL instruments from 1990 to 2010, categorized, and reviewed the properties of the instruments using international guidelines as reference. Of the 2766 articles retrieved, 710 met the inclusion criteria and used 57 different head and neck-specific instruments to assess QOL. A review of the properties of these utilized measures and identification of areas in need of further research is presented. Given the volume and heterogeneity of QOL measures, there is no gold standard questionnaire. Therefore, when selecting instruments, researchers should consider not only psychometric properties but also research objectives, study design, and the pitfalls and benefits of combining different measures. Although great strides have been made in the assessment of QOL in HNC and researchers now have a plethora of quality instruments to choose from, more work is needed to improve the clinical utility of these measures in order to link QOL research to clinical practice. This review provides a platform for head and neck-specific instrument comparisons, with suggestions of important factors to consider in the systematic selection of QOL instruments, and is a first step towards translation of QOL assessment into the clinical scene.

Bisphosphonate-related osteonecrosis of the jaws – A review - Corrected Proof

2012-04-23

Summary: The aim was to evaluate the knowledge about bisphosphonate-related osteonecrosis of the jaws (BRONJ). A bibliographic search in Medline, PubMed and the Cochrane Register of controlled clinical trials was performed between 2003 and 2010 by using the terms bisphosphonate and osteonecrosis of the jaw. The amount of publications per year, the type of journal for publication, and the evidence level of the trial were evaluated. Next to this the incidences and the success of treatment strategies for BRONJ were identified. A total of 671 publications were reviewed. Since 2006 more than 100 publications on BRONJ per year (with an upward trend) have been published, mostly in dental journals. The evidence level could be determined for 176 publications and only one grade Ia study was found. The studies showed a wide variety in design, most of them being retrospective. The incidence of BRONJ is strongly dependent on oral or intravenous application and varies between 0.0% and 27.5%. There is no scientific data to sufficiently support any specific treatment protocol for the management of BRONJ. Further clinical studies are needed to evaluate the incidence and treatment strategies at a higher level of evidence. Therefore uniform study protocols would be favourable.

Distant metastases from head and neck squamous cell carcinoma. Part I. Basic aspects - Corrected Proof

2012-04-20

Summary: The incidence of distant metastasis in head and neck squamous cell carcinoma (HNSCC) is relatively low but remains a major determinant of prognosis and therefore an important factor in clinical decision making. The most frequently involved sites for distant metastasis are the lung (approximately 70% of cases), followed by bone and liver. There are often conflicting reports on which parameters are risk factors for distant metastasis, but the most important predictive factors appear to be the site of the primary tumor (hypopharynx in particular), advanced T- and N-classification, histological grade and the ability to achieve locoregional disease control. Metastasis results from a selection of tumor cells that have acquired the properties to withstand multiple and often unfavorable circumstances and settle in distant organs. Most of these processes involve interaction between tumor cells, their microenvironment and host factors. Increasing knowledge of the biology of distant metastasis may result in the development of diagnostic and therapeutic strategies targeted to this usually terminal stage for patients with HNSCC.

Distant metastases from head and neck squamous cell carcinoma. Part II. Diagnosis - Corrected Proof

2012-04-20

Summary: The detection of distant metastases is critical for prognostication and for the choice of treatment in patients with head and neck squamous cell carcinoma (HNSCC). Pretreatment screening for distant metastases should be conducted particularly for patients with high risk factors, prior to locoregional treatment decisions. Different diagnostic techniques are discussed. Unfortunately, most studies lack sufficient follow-up to reliably assess false-negative results. Moreover, the designs of most studies vary substantially with regard to homogeneity of groups (tumor types and stages), timing (pretreatment, follow-up) and definition of risk factors (patient selection). Therefore, only a few studies are comparable. The combination of F-18 fluoro-d-glucose-positron emission tomography (FDG-PET) and a dedicated CT (at least of the chest) is the most important imaging protocol at the present time. Eventually, whole-body-MRI (WB-MRI) may possibly replace PET-CT for screening patients for distant metastases.

One-step nucleic acid amplification for detecting lymph node metastasis of head and neck squamous cell carcinoma - Corrected Proof

2012-04-20

Summary: Objectives: Lymph node stage is an important prognostic factor in head and neck squamous cell carcinoma (HNSCC). We previously reported the clinical usefulness of sentinel lymph node biopsy diagnosed by genetic analysis using quantitative RT-PCR. However, this method takes about 3h. In this study, we attempted to develop a more efficient method for the intraoperative genetic detection of lymph node metastasis in HNSCC.Materials and methods: A total of 312 lymph nodes (65 patients) were diagnosed by the one-step nucleic acid amplification (OSNA) method using GD-100. OSNA consists of a short homogenization step followed by amplification of cytokeratin 19 (CK19) mRNA directly from the lysate. Each lymph node was divided into two to diagnose metastasis. One half was used for the OSNA assay, and the other was subjected to semi-serial sectioning, sliced at 200-μm intervals and examined by H&E and cytokeratin AE1/AE3 immunohistochemical staining. The accuracy of OSNA assay was evaluated based on histopathological diagnosis.Results: Sixty-one of 312 lymph nodes were pathologically metastasis-positive. The overall concordance rate between the OSNA assay using breast cancer criteria and histopathology was 94.2%. The optimal cut-off for the copy number of CK19 mRNA in assessing lymph node metastasis of HNSCC was 300copies/μl, which had the highest diagnostic accuracy (95.2%). The OSNA assay can be completed within 30min.Conclusion: The OSNA assay, which shows high sensitivity and specificity, suggests the possibility to be used as a novel tool for the genetic detection of lymph node metastasis in HNSCC patients.

Primary chemoradiotherapy for oral cavity squamous cell carcinoma - Corrected Proof

2012-04-20

Summary: Objectives: To evaluate the survival of patients with oral cavity squamous cell carcinoma (SCC) treated with chemoradiotherapy (CRT) or radiotherapy (RT). To record the rate of osteoradionecrosis (ORN) and need for alternative feeding of patients with oral cavity cancer treated with CRT or RT.Materials and methods: All patients with first presentation of oral cavity SCC treated with CRT or RT only at the Royal Brisbane & Women’s Hospital (RBWH) between 2000 and 2007 were included. Patient Demographics (age, sex), ACE-27 Co-morbidity index, Staging (TNM staging system), Type of Chemotherapy and Dose of RT, Overall Survival (OS) and Disease-Specific Survival (DSS), Attempt at Salvage, development of distant metastases, development of ORN and success of treatment for ORN and requirement for alternative feeding (PEG/NGT) were recorded.Results: Fifty-four patients met the inclusion criteria. One patient died due to toxicity of treatment. The 5-year OS was 29%. The 5-year DSS was 30%. The rate of ORN amongst survivors was 36%.Conclusions: CRT is successful in a small number of patients with oral cavity SCC. When compared to the published literature, surgery with or without post-operative RT has better survival rates. Salvage surgery does not appear to be a viable option for management of recurrence post CRT. The consequences of treatment, namely ORN and need for alternative feeding, are high.

Distant metastases from head and neck squamous cell carcinoma. Part III. Treatment - Corrected Proof

2012-04-19

Summary: Distant metastases from head and neck squamous cell carcinoma (HNSCC), though rare at initial presentation, remain an important manifestation of cancer recurrence and mortality. Although generally considered incurable with a dismal prognosis despite palliative therapy, highly selected patients with distant metastases may have a long term survival benefit from aggressive surgery or radiotherapy. Advances in systemic treatments also may improve patient survival. This article reviews the current state of management of HNSCC patients with distant metastases.

Oral dysplasia and squamous cell carcinoma: Correlation between increased expression of CD21, Epstein-Barr virus and CK19 - Corrected Proof

2012-04-18

Summary: Objectives: Epstein-Barr virus is an orally transmitted human gammaherpesvirus that infects B lymphocytes and epithelial cells. Although most primary infections are asymptomatic, long term carriage of the virus can be associated with either lymphoid or epithelial malignancies. The association of EBV with oral squamous cell carcinomas is sporadic and it is uncertain if the virus is involved in initiation of the tumor or, possibly, in its progression. Complement receptor type 2, CR2 or CD21, is a receptor for the major attachment protein of EBV, which significantly enhances epithelial cell infection, but its expression on normal tissues is restricted to tonsil and adenoid epithelium. As cells become dysplastic they are reported to express higher levels of CK19. We sought to evaluate whether CD21 and CK19 expression change as oral epithelial cells outside Waldeyer’s ring become dysplastic.Materials and methods: Epithelial cells were isolated by laser capture microdissection and levels of CD21, CK19 and EBV RNA were measured by quantitative reverse transcriptase PCR.Results: We report that expression of CD21 increases in frequency and intensity as oral epithelial cells become more dysplastic and that expression correlates with an increase in infection by EBV. Tumors or dysplastic lesions that carry EBV also generally express higher levels of CK19 than those that do not.Conclusion: The findings suggest that dysplasia may make cells more susceptible to infection by EBV and that infection by the virus may alter the phenotype of the infected cell in a manner which could affect prognosis.

Oral microbial carriage in oral squamous cell carcinoma patients at the time of diagnosis and during radiotherapy – A comparative study - Corrected Proof

2012-04-18

Summary: Objectives: Tobacco chewing habit, presence of squamous cell carcinoma in oral cavity and radiotherapy causes alterations in healthy oral microflora. Abnormal flora developed due to radiotherapy in oral squamous cell carcinoma (OSCC) patients can exacerbate mucositis and can cause systemic infections.The role of oral microorganisms in carcinogenesis is gaining interest recently. Abnormal flora in development of second tumor in the field of first tumor is to be established. The study fundamentally tries to evaluate the shift that occurs during the radiotherapy in OSCC patients.Methods: Microbial analysis of saliva samples from OSCC patients undergoing radiotherapy, tobacco chewers and controls was undertaken. The microorganisms were grouped into categories as total aerobes, total anaerobes, candida, coliforms and gram negative anaerobic bacteria.Results: The frequency of isolation of total aerobes, total anaerobes, coliforms and gram negative anaerobic bacteria was significantly high in OSCC patients compared to healthy controls whereas candida was isolated most frequently during radiation period.The tobacco chewers showed significant increase in colony forming units of total aerobes and coliforms. All the microbial groups were high in OSCC and radiotherapy patients. While OSCC patients showed significant increase in total anaerobes and gram negative anaerobes, candida was increased in radiotherapy patients only.Conclusion: Habits promote coliforms. Tumor supports efficiently anaerobes and candida. The latter is supported more by radiation. The study stresses the importance on administration of appropriate antimicrobial therapy right at the time of diagnosis of the lesion.

Phase II study of gefitinib adaptive dose escalation to skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck - Corrected Proof

2012-04-18

Summary: Background: Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome.Methods: This open-label, multi-institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750mg to achieve the skin toxicity grade ⩾2.Results: Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade ⩾2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33patients. Median progression-free survival was 1.9months (95% CI 1.6–2.2) and median overall survival was 5.1months (95% CI 2.4–7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival.Conclusions: Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity.

The value of tumor diameter in predicting prognosis of oropharynx cancer treated with chemoradiation - Corrected Proof

Matthew C. Ward, Ling Lan, Amy Y. Chen, Jonathan J. Beitler — 2012-04-16

Summary: Objectives: The tumor node metastasis (TNM) system is the most widely used staging system for cancers of the oropharynx, yet is known to omit key prognostic indicators. Tumor volume has been shown in other head and neck sites to add predictive power but is not as useful in the oropharynx. This study investigates the value of other methods in quantifying tumor burden.Methods: Treatment plans of oropharyngeal cancer patients treated non-operatively were retrospectively reviewed. Potential prognostic factors including TNM, demographics, smoking history, and various tumor dimensions were analyzed.Results: Records identified 93 patients treated with definitive concurrent chemoradiation who had at least one year of follow-up and a clear GTV contour on the original treatment plan. On univariate analysis, tumor diameter and tumor volume showed a significant relationship to overall and disease-free survival. Tumor stage, age and smoking history showed significance in regard to overall survival. On multivariate analysis tumor diameter showed independent significance but not TNM or tumor volume.Conclusion: Our method of measuring tumor diameter has independent prognostic significance in the oropharynx where GTV has shown questionable value.

Genome-wide disease association study in chewing tobacco associated oral cancers - Corrected Proof

Renu Bhatnagar, Jyoti Dabholkar, Dhananjaya Saranath — 2012-04-16

Summary: With a view to identify genomic risk variants in chewing-tobacco associated oral cancer patients, a genome-wide association study was conducted in patients of Indian ethnicity with long term tobacco chewing habit.We analyzed 55 oral cancer patients and 92 healthy controls for single nucleotide polymorphisms, using high throughput microarray Illumina Infinium II Assay platform and Human CNV370k-bead chip containing 370,000 single nucleotide polymorphisms.The PLINK software platform defined 298 SNPs with minor allele frequency of several genes significantly increased in oral cancer patients as compared to the controls (p<0.001). Illumina Genome Viewer Software Version 3.2.9, further delineated 93 SNPs with p-values ranging from 9.3×10–4 to 1.38×10–5 and Odd’s ratio of 2.18–8.48, associated with 70 genes. Analysis using Kyoto Encyclopedia of Genes and Genome Pathway database, indicated SNP association with several genes including GRIK2, RASGRP3, CAMK4, SYK, RAPTOR, FHIT, DCC, active in signal transduction; MMP2, CNTNAP2, PTPRJ associated with tumor cell migration; and apoptotic gene IRAK3.The data indicates an inherent role for the genetic constitution of individuals in oral carcinogenesis, with the genomic variants contributing to increased risk or susceptibility to oral cancer.

Functional single-nucleotide polymorphisms in the BRCA1 gene and risk of salivary gland carcinoma - Corrected Proof

Li Xu, Phi C. Doan, Qingyi Wei, Guojun Li, Erich M. Sturgis — 2012-04-16

Summary: Objectives: Polymorphic BRCA1 is a vital tumor suppressor gene within the DNA double-strand break repair pathways, but its association with salivary gland carcinoma (SGC) has yet to be investigated.Materials and methods: In a case–control study of 156 SGC patients and 511 controls, we used unconditional logistical regression analyses to investigate the association between SGC risk and seven common functional single-nucleotide polymorphisms (A1988G, A31875G, C33420T, A33921G, A34356G, T43893C and A55298G) in BRCA1.Results: T43893C TC/CC genotype was associated with a reduction of SGC risk (adjusted odds ratio=0.55, 95% CI: 0.38–0.80, Bonferroni-adjusted p=0.011), which was more pronounced in women, non-Hispanic whites, and individuals with a family history of cancer in first-degree relatives. The interaction between T43893C and family history of cancer was significant (p=0.009). The GATGGCG and AACAACA haplotypes, both of which carry the T43893C minor allele, were also associated with reduced SGC risk.Conclusion: Our results suggest that polymorphic BRCA1, particularly T43893C polymorphism, may protect against SGC.

Low Level Helium Neon Laser therapy for chemoradiotherapy induced oral mucositis in oral cancer patients – A randomized controlled trial - Corrected Proof

2012-04-13

Summary: Background: Patients receiving chemoradiotherapy (CRT) for oral cancer (OC) often develop oral mucositis (OM). OM associated pain severely affects oral functions and nutrition of the patient, resulting in narcotic analgesic use and CRT interruption. Laser therapy has shown some promising results in preventing and treating OM caused by cancer therapies. So in this trial we used prophylactic Low Level Helium Neon (He–Ne) Laser for the prevention and treatment of CRT induced OM in OC patients.Materials and methods: This double blinded trial block randomized 121primary OC patients scheduled to undergo CRT [RT dosage=66Gray/33fractions for 5days/week and chemotherapy (3 weekly Cisplatin)] into laser (n=60) and placebo (n=61) group. Laser group received He–Ne Laser (λ=632.8nm, P=24mW, ED=3.5J/cm2) while placebo received sham treatment just before radiation for 6.5weeks. OM (RTOG/EORTC Scale), its associated pain, and total parenteral nutrition (TPN), were assessed on every week by a blinded assessor. Also opioid analgesic use, weight loss and any CRT break were recorded. Data was analyzed using descriptive statistics, t-test and Man Whitney U test. Level of significance was set at p<0.05.Results: Incidence of severe OM (29% vs. 89%, p<0.001) and its associated pain (18% vs. 71%, p<0.001), opioid analgesic use (7% vs. 21%, p<0.001)and TPN (30% vs. 39% p=0.039) was significantly less in laser than placebo group patients. Also duration of severe OM and pain experienced was less in laser than placebo group. CRT break required only for placebo group (9%) patients.Conclusion: Low Level He–Ne Laser decreased the incidence of CRT induced severe OM and its associated pain, opioid analgesics use and TPN.

Global quality of life during the acute toxicity phase of multimodality treatment for patients with head and neck cancer: Can we identify patients most at risk of profound quality of life decline? - Corrected Proof

2012-04-13

Summary: Purpose: Treatment intensification has improved outcomes for patients with head and neck cancer (HNC), but little has been reported on health-related quality of life (QoL) consequences. We investigated changes in QoL after (chemo)radiotherapy to identify patient characteristics that predict those whose QoL deteriorates most profoundly in the acute post-treatment period.Materials and methods: Patients with locally advanced HNC treated with curative intent received intensity-modulated radiotherapy (60–70Gy) in this prospective study. (Chemo)radiotherapy was either definitive or adjuvant. Induction chemotherapy consisted of three cycles of docetaxel, cisplatin, and 5-fluorouracil; responders received (chemo)radiotherapy; nonresponders underwent salvage surgery followed by (chemo)radiotherapy if appropriate. Patients completed the EORTC QLQ-C30 and HNC-specific HN35 module before and at the end of (chemo)radiotherapy and 6–8weeks after therapy completion.Results: Ninety-five patients participated. At baseline, patients reported significantly lower Global health status, functioning, and symptom scale scores than a reference German population (all p<0.001). At the end of (chemo)radiotherapy, patients had significantly lower QoL scores vs. baseline on all functioning scales (p<0.05). Most symptom and HN35 scores worsened during (chemo)radiotherapy but many recovered 6–8weeks post-treatment. QoL deteriorated more in patients with high vs. low baseline QoL; no clinical or sociodemographic characteristics of patients most likely to experience a significant deterioration in QoL during treatment were identified.Conclusion: These standard QoL instruments did not predict patients at risk of profound global QoL impairments during acute treatment. Other than baseline QoL, no patient characteristics associated with significant QoL deterioration were identified.

Biopsy vs. brushing: Comparison of two sampling methods for the detection of HPV-DNA in squamous cell carcinoma of the oral cavity - Corrected Proof

N. Termine, L. Giovannelli, V. Rodolico, D. Matranga, G. Pannone, G. Campisi — 2012-04-12

Summary: Background: HR HPV infection was proposed as aetiological factor of oral squamous cell carcinomas (OSCC). HPV frequency in OSCC is highly variable, due to the discrepancy in oral sampling procedures, HPV testing methods and inclusion criteria regarding tumour site (strictly oral cavity vs. nearby structures). Our aim was to compare HPV DNA frequency and type-specific distribution in paired cytological and histological samples of SCC strictly located in oral cavity. The correlation between HPV detection rate by each method of sampling and demographical, behavioural and clinical–pathological variables was also examined.Patients and methods: HPV DNA was detected in brushed cells and formalin-fixed paraffin-embedded biopsies obtained from 83 consecutive unselected immunocompetent adults with OSCC. HPV DNA detection was performed in all samples by nPCR followed by direct DNA sequencing and the assay INNO-LiPA HPV Genotyping. Univariate and multivariate statistics were used, including Cohen κ index to evaluate agreement between two methods and association between HPV infection and demographical, behavioural and clinical–pathological variables for each method of sampling (p<0.05 statistically significant).Results: HPV DNA was detected in 15.7% (13/83) of brushings and 12.1% (10/83) of biopsies (p>0.05). High risk HPV 51, 16 and 39 were genotypes more frequently detected, especially among biopsies; no concordance between two methods was found (Cohen κ index=0.04, p=0.34).Conclusion: A fraction of OSCC could be linked to HR HPV infection in the Mediterranean area. Although without a statistical significance, biopsy specimen demonstrated more accurate for HR HPV detection than brushing in OSCC.

Postoperative morbidity in head and neck cancer ablative surgery followed by microsurgical free tissue transfer in the elderly - Corrected Proof

2012-04-12

Summary: Objective: To identify the risk factors for postoperative morbidities in elderly patients (≧65 years old) who underwent head and neck tumor ablation followed by immediate free tissue transfer.Methods: We performed a retrospective analysis of 1012 patients who underwent free tissue transfer after head and neck cancer ablation between 2007 and 2010. A total of 167 patients aged 65 and older were identified. These patients were divided into two age-related subgroups: patients aged between 65 and 70 years in one cohort and patients older than 70 years in the second cohort. The demographic and operative variables as well as postoperative medical and surgical morbidities were analyzed.Results: The older group had significantly prolonged ICU stay (p = 0.014) and hospital stay (p = 0.039). The same group also had higher rates of intraoperative blood transfusion ≧2 units (p = 0.019), unplanned reintubation (p < 0.001), medical (p = 0.004), and surgical (p < 0.001) complications. The intraoperative blood loss of >220 mL was a significant predictive factor for postoperative medical morbidities (odds ratio [OR] 2.25; 95% confidence interval [CI], 1.01–5.03; p = 0.048). The age of >70 years was an independent risk factor for postoperative medical and surgical morbidity (OR [95% CI]: 4.08 [1.67–9.99] and 3.48 [1.56–7.78], p = 0.002, respectively).Conclusions: Age over 70 years and intraoperative blood loss of >220 mL are significant risk factors for predicting postoperative morbidity, and a thorough pre-treatment evaluation and care for elderly patients are required.

Tooth extraction in patients on zoledronic acid therapy - Corrected Proof

Marco Mozzati, Valentina Arata, Giorgia Gallesio — 2012-04-09

Summary: Objectives: Surgical management of patients following zoledronic acid therapy is particularly difficult, since the dental extraction is the main cause of BRONJ.Methods: A case-control study was conducted on 176 patients treated with intravenous (IV) bisphosphonates for oncologic pathologies who also underwent dental extractions. The study was divided randomly into two groups: 91 were treated with Plasma Rich in Growth Factor Plasma (PRGF) (study group) and the other 85 were not treated with the growth factor preparation (control group).Results: Panoramic X-ray and computed tomography were performed both before and 60months after surgery. By clinical and radiological diagnosis, BRONJ was diagnosed in only 5 patients in the control group at an average of 91, 6days after tooth extraction.Conclusions: We hypothesize that Plasma Rich in Growth Factor (PRGF) is important for the successful treatment of patients on bisphosphonates to restore the osteoblast/osteoclast homeostatic cycles via autologous cytokines. Moreover, this protocol reduces the risk of BRONJ when it is necessary to perform dental extractions in patients undergoing IV bisphosphonate treatment.

Trends in salivary diagnostics – A 5-year review of Oral Oncology (2007–2011) - Corrected Proof

Akhil A. Shankar, Samapika Routray — 2012-04-09

To The Editor-in-Chief, Oral squamous cell carcinoma (OSCC) presents as a menacing problem throughout the world. Although adequate emphasis has been placed on early diagnosis, newer diagnostic modalities are always welcome as they provide a more enhanced and sensitive approach in diagnosing the disease, and hence nipping it in the bud. Saliva has been considered to be a minefield of biomarkers, and has obviously been translated into one of the most versatile tools for diagnosis of various diseases, with an added advantage; these biomarkers also aid in the treatment evaluation as well as monitoring of the patients post treatment, with the least possible discomfort caused to the patient, as well as the doctor.

KRAS and BRAF mutations in sinonasal cancer - Corrected Proof

2012-03-29

Summary: Objetives: Despite improvements in the field of surgery and radiotherapy, the overall prognosis of sinonasal carcinomas is poor, mainly due to the difficulty to resect the tumour completely in this anatomically complex region. Therefore, there is great need for alternative treatments. Knowledge of the KRAS and BRAF mutational status would become clinically important with regard to the possible use of anti-EGFR therapies.Material and methods: DNA was extracted from paraffin embedded tumour samples from 57 cases of sinonasal squamous cell carcinoma (SNSCC) and from fresh frozen tumour samples from 58 cases of intestinal-type sinonasal adenocarcinoma (ITAC). Point mutations were analysed for KRAS exon 2 (codons 12 and 13) and BRAF (exon 15, V600E) by direct sequencing.Results: Neither KRAS nor BRAF showed any mutations in the SNSCC, whereas 7/58 (12%) ITAC harboured KRAS mutations and no BRAF mutations. All seven cases with KRAS mutation concerned well-differentiated and less aggressive (papillary and colonic type) ITAC, all patients being woodworkers and 4/7 tobacco smokers.Conclusion: Neither of SNSCCs carried mutations in KRAS and BRAF and a low frequency of KRAS mutation was found in ITAC. This suggests that KRAS and BRAF mutations play a limited role in the development of sinonasal cancer and that mutation analysis is not useful as a screening test for sensitivity to anti-EGFR therapy in sinonasal cancer.

Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis - Corrected Proof

2012-03-29

Summary: We summarized existing evidence about whether the aberrant E-cadherin expression is a prognostic factor for patients with HNSCC. Identifying relevant articles, filtrating studies and extracting data were independently conducted by two reviewers. The quality of eligible studies was assessed according to systematic score criteria. Associations between aberrant E-cadherin expression and overall survival (OS) or disease-free survival (DFS) were summarized by hazard ratio (HR) estimates. Random or fixed effects models were used to investigate the effect of E-cadherin across the studies. According to the multivariate and univariate analyses, the meta-analysis of the included studies gave a statistically significant pooled HR for OS in HNSCC [the pooled HR=2.533; 95% confidence interval (CI)=1.971–3.254]. In addition, the subgroup analyses showed that the pooled HR of each subgroup also exhibited statistical significance according to the subpopulations (Asian and other subpopulations), treatments (surgery and other treatments), locations of primary tumors (oral cavity and other subsites), and data sources of HR (reported and estimated HR). Similar to the results of OS, the analysis of four included trials showed that the aberrant E-cadherin expression could predict low DFS. Meanwhile, a cumulative meta-analysis showed that the pooled HR became statistically significant. However, a meta-regression analysis showed that the OS was not statistically significant with the cutoff values of the included studies. Our study gives an important piece of evidence that aberrant E-cadherin expression was associated with a poor prognosis in patients with HNSCC.

Oral potentially malignant disorders: Precising the definition - Corrected Proof

Sachin C. Sarode, Gargi S. Sarode, Jagdish V. Tupkari — 2012-03-29

Definitions form the integral part of medical literature. Many had undergone refinement in the literature for the pursuance of correct, clear, uniform and unambiguous definition. This quest is necessary for precising the definition which must reflect the most advanced scientific understanding of the concept and adhere to the best available knowledge-representation principle.

Clinical outcome for nasopharyngeal carcinoma with predominantly WHO II histology treated with intensity-modulated radiation therapy in non-endemic region of China - Corrected Proof

2012-03-26

Summary: Objectives: To evaluate the clinical outcomes of using intensity-modulated radiotherapy (IMRT) in the primary treatment of nasopharyngeal carcinoma (NPC) in Northwest China, including assessments of failure patterns, toxicities and potential prognostic factors.Methods and materials: Between January 2006 and June 2010, 193 newly diagnosed non-metastatic NPCs were treated by IMRT with simultaneous-integrated boost (SIB) technique in Xijing Hospital of Northwest China. Cisplatin-based chemotherapy was offered to 85.5% patients. Acute and late toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) scoring criteria. Prognostic factors were assessed by univariate or multivariate analysis. Statistical analyses were performed on survival and failure patterns.Results: Median follow-up was 34months. WHO type II was the predominant histology for NPCs (69.9%) in our study group. Twelve patients experienced local regional failure and total distant metastasis occurred in 34 patients, representing the major mode of failure. The 3-year local recurrence-free (LRFS), regional recurrence-free (RRFS), distant metastasis-free (DMFS) and overall survival (OS) rates were 86.6%, 86.7%, 86.4%, and 85.7%, respectively. Multivariate analyses showed N-classification, age (⩽50 vs. >50) and WHO type (WHO II vs. WHO III) were independent predictors for DMFS, LRFS and OS. Tumor volume (⩽50cm3 vs. >50cm3) and presence of anemia were independent significant prognostic factors for profession-free survival (PFS). No significant difference was observed between different T categories. Acute and late toxicities were mild or moderate. No grade IV toxicities were observed.Conclusions: WHO II was the predominant histology and a significant poor prognostic factor in our study group, indicating different carcinogenetic pathways of NPC between endemic and non-endemic regions. Our experience of using IMRT in the treatment of NPC in non-endemic region showed excellent locoregional control and favorable toxicity profiles.

The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation - Corrected Proof

2012-03-23

Summary: Objectives: The PI3K/AKT/mTOR signalling axis controls cell proliferation and survival and has achieved major importance as a target for cancer therapy. This investigation evaluated the expression of the major components P-AKT, P-mTOR, PI3K and P-S6rp in salivary gland cancer.Materials and methods: Immunohistochemical expression of P-AKT, P-mTOR, PI3K and P-S6rp was evaluated and correlated to clinicopathological parameters and survival of 272 patients with salivary gland carcinomas.Results and conclusion: Analysis of all tumours together revealed an increased expression of all components of the pathway in comparison to normal salivary gland control tissue. Nuclear expression of P-AKT was associated with young age, localised tumour stage, absence of lymph node metastases and favourable prognosis. On the contrary, cytoplasmic P-AKT displayed unfavourable tumour characteristics like high-grade malignancy, and worse overall survival. In comparison to cytoplasmic/membrane mTOR expression, nuclear P-mTOR was associated with absence of lymph node metastases and higher survival rates. PI3K and P-S6rp were exclusively found in the cytoplasm. Expression of P-S6rp was correlated to increased age, advanced tumour size and lymph node metastases. In all tumours together, nuclear P-AKT positively correlated with nuclear P-mTOR, whereas P-S6rp was associated with expression of PI3K and cytoplasmic P-AKT. In acinic cell carcinoma, cytoplasmic expression of P-AKT, P-mTOR, PI3K and P-S6rp was positively associated with each other.In conclusion, PI3K/AKT/mTOR signalling is active in salivary gland cancer and might function as a target for personalised therapy. P-AKT and P-mTOR possess distinct molecular functions with impact on prognosis depending on their cellular localisation.

Association of periodontitis with the risk of oral leukoplakia - Corrected Proof

Peter Meisel, Birte Holtfreter, Reiner Biffar, Wolfgang Suemnig, Thomas Kocher — 2012-03-21

Summary: Background: Oral leukoplakia is an oral lesion suspected to be of premalignant character. Besides smoking and alcohol, the risk factors for the development of this oral lesion are still less identified. The purpose of this study was the search for a possible influence of periodontitis on the risk of leukoplakia.Methods: We used data from 4233 subjects (2116 women and 2117 men) who were recruited for the population-based Study of Health in Pomerania (SHIP) and finished a standard medical and dental examination. One hundred two-three cases with oral leukoplakia were 1:2 age and sex-matched with 246 healthy control subjects. Measures of bleeding on probing and clinical attachment loss were related to oral leukoplakia.Results: We found increased periodontal measures in subjects with leukoplakia. Adjusting for risk factors and possible confounders revealed a periodontitis-related dose-dependent increase in the probability of having oral leukoplakia. Odds ratios adjusted for socioeconomic factors and smoking computed for the second, third and fourth quartiles of clinical attachment loss were OR=1.7 (0.6–5.0), 3.3 (0.8–13.1) and 5.3 (1.2–22.7), respectively. For bleeding on probing the respective odds ratios were OR=2.0 (0.8–4.90), 2.9 (1.1–7.8) and 3.8 (1.5–9.8), respectively. Measures of systemic inflammation and of lipid metabolism were important cofactors attenuating these figures. While smoking is a risk factor of leukoplakia, oral hygiene is protective. In a follow-up survey, the leukoplakia subjects had lost more teeth than their counterparts (p=0.043).Conclusion: Periodontitis increases the risk of oral leukoplakia and, therefore, the risk of mucosal lesions predisposing to oral cancers.

Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx and hypopharynx - Corrected Proof

2012-03-21

Summary: Objectives: Significant laryngeal edema (SLE) after radiotherapy for squamous cell carcinoma of the larynx and hypopharynx may be associated with upper airway obstruction or tumor recurrence. We assessed the risk factors predictive of SLE and those differentiating tumor recurrence from SLE.Patients and methods: We evaluated 127 patients with laryngohypopharyngeal squamous cell carcinomas who were primarily treated with radiotherapy with/without chemotherapy, had no previous major head and neck surgery, and underwent laryngoscopic examinations after radiotherapy. SLE was defined as RTOG grades ⩾2 and patient characteristics and imaging, treatment and survival results were compared in patients with and without SLE.Results: Of the 127 patients, 56 (44%) had SLE. Univariate analyses showed that tumor location, T and N classifications, overall stage, pathologic differentiation, and chemotherapy were significantly predictive of SLE (P<0.05). Multivariate analysis revealed that T classification remained an independent predictor of SLE (T1 vs. T2–4; odds ratio=5.070, 95% confidence interval=1.999–12.857; P=0.001). Twenty-seven (21%) patients had tumor recurrences, diagnosed by PET/CT (sensitivity 88%; specificity 92%) and CT (sensitivity 68%; specificity 88%). Twenty-seven patients with severe SLE were treated but only 9 (33%) had improvement. Tumor recurrence rate was higher (39% vs. 7%, P<0.001) and 3-year overall survival rate lower (54% vs. 87%, P<0.001) in patients with than without SLE.Conclusion: Patients with T2–4 laryngohypopharyngeal cancers are at higher risk of SLE development and tumor recurrence after radiotherapy that can be properly detected by 18F-FDG PET/CT.

Cutaneous head and neck basal and squamous cell carcinomas with perineural invasion - Corrected Proof

2012-03-19

Summary: Perineural invasion (PNI) occurs in 2% to 6% of cutaneous head and neck basal and squamous cell carcinomas (SCCs) and is associated with mid-face location, recurrent tumors, high histologic grade, and increasing tumor size. Patients may be asymptomatic with PNI appreciated on pathologic examination of the surgical specimen (microscopic), or may present with cranial nerve (CN) deficits (clinical). The V and VII CNs are most commonly involved. Magnetic resonance imaging (MRI) may be obtained to detect and define the extent of PNI; computed tomography (CT) or ultrasound-guided fine needle aspiration cytology (UGFNAC) may assist with detecting or excluding regional lymph node metastases. Patients with apparently resectable cancers undergo surgery, usually followed by postoperative radiotherapy (RT). Patients with unresectable cancers are treated with definitive RT. Moreover, RT may be considered if significant functional or cosmetic impairment is expected after surgical treatment. The 5-year outcomes after treatment for clinically unsuspected microscopic compared with clinical PNI are: local control, 80% and 55%; cause-specific survival, 75% and 65%; and overall survival, 55% and 50%, respectively. The incidence of grade ⩾3 complications is higher after treatment for clinical PNI versus microscopic PNI; approximately 35% compared with 15%, respectively. Proton beam RT may be used to reduce the risk of late complications by reducing RT dose to the visual apparatus and central nervous system (CNS).

Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinoma - Corrected Proof

2012-03-19

Summary: Objectives: MicroRNA deregulation is a critical event in head and neck squamous cell carcinoma (HNSCC). Several microRNA profiling studies aimed at deciphering the microRNA signatures of HNSCC have been reported, but there tends to be poor agreement among studies. The objective of this study was to survey the published microRNA profiling studies on HNSCC, and to assess the commonly deregulated microRNAs in an independent sample set.Materials and methods: Meta-analysis of 13 published microRNA profiling studies was performed to define microRNA signatures in HNSCC. Selected microRNAs (including members of miR-99 family) were evaluated in an independent set of HNSCC cases. The potential contributions of miR-99 family to the tumorigenesis of HNSCC were assessed by in vitro assays.Results: We identified 67 commonly deregulated microRNAs. The up-regulation of miR-21, miR-155, miR-130b, miR-223 and miR-31, and the down-regulation of miR-100, miR-99a and miR-375 were further validated in an independent set of HNSCC cases with quantitative RT-PCR. Among these validated microRNAs, miR-100 and miR-99a belong to the miR-99 family. Our in vitro study demonstrated that restoration of miR-100 to the HNSCC cell lines suppressed cell proliferation and migration, and enhanced apoptosis. Furthermore, ectopic transfection of miR-99 family members down-regulated the expression of insulin-like growth factor 1 receptor (IGF1R) and mechanistic target of rapamycin (mTOR) genes.Conclusion: In summary, we described a panel of frequently deregulated microRNAs in HNSCC, including members of miR-99 family. The deregulation of miR-99 family contributes to the tumorigenesis of HNSCC, in part by targeting IGF1R and mTOR signaling pathways.

Nasopharyngeal carcinoma: Salvage of local recurrence - Corrected Proof

Anne W.M. Lee, Willard E. Fee, W.T. Ng, L.K. Chan — 2012-03-16

Summary: Local control of nasopharyngeal carcinoma has substantially improved with advancing radiotherapy technology and appropriate combination with chemotherapy. However, when local recurrence occurs, this is one of the most difficult challenges. Aggressive treatment is indicated because long term salvage is achievable particularly for early recurrence, but high risk of complications is a serious concern. Treatment options include different methods of surgery and/or re-irradiation with/without chemotherapy. Available information in the literature is grossly inadequate; most reports compose of small series of highly selected patients with heterogeneous characteristics and treatment. No randomized trials have been performed to evaluate the therapeutic ratio of different treatment methods. This article reviews available treatment options, their therapeutic benefits and risks of complications; the objective is to provide information for developing treatment recommendations and suggestions for future improvement.

Mucosal Disorders with Oral Epithelial Dysplasia risk – Development of a simple screening tool for general health care setting - Corrected Proof

Valsa Thomas, S. Rema Devi, Visalakshi Jeyaseelan, L. Jeyseelan — 2012-03-15

Summary: Objectives: Oral visual screening can avert oral cancer mortality. Oral premalignancies are currently considered as separate, individual disorders. The objective was to develop a simple clinical screening tool to detect oral premalignancies in general health care setting and validate diagnostic accuracy against Oral Medicine specialist examination as gold standard.Materials and methods: All steps in development of new tool, from item generation to item selection and item reduction were carried out. Item generation was done using qualitative methods. After pre-testing and piloting, junior dental house surgeon administered the refined tool, to patients attending dental outpatient department (n=255). Subsequent evaluation by an Oral Medicine specialist using consensus clinical criteria, detected 59 screen positive cases. Each case was recoded as per scores assigned by binary logistic regression coefficients and total score computed. The Receiver Operator Characteristic (ROC) was performed against specialist examination as gold standard. Performance ability and reliability coefficient of final tool was assessed. A simple score was assigned to indicate stage and clinical severity.Results: Screening Tool for Oral Premalignancies (STOP) has sensitivity 96.6%, specificity 99.0% and accuracy 98.4% with reliability coefficient 0.874. Scores detect clinical signs and staging reflect clinical severity alerts.Conclusion: Oral Potentially Malignant Disorders need to be evaluated as single entity, under a common umbrella – Mucosal Disorders with Oral Epithelial Dysplasia risk (MD-OEDr). STOP is a simple tool for opportunistic general health care screening of MD-OEDr.

Comment on “Tumour infiltration depth P4 mm is an indication for an elective neck dissection in pT1cN0 oral squamous cell carcinoma” by Melchers et al., Oral Oncol (2011). doi:10.1016/j.oraloncology.2011.11.007 - Corrected Proof

Supriya M. Kheur, Samapika Routray — 2012-03-15

To the Editor, As suggested in the article by Melchers et al. tumor infiltration depth can certainly be used as an independent predictor for nodal metastasis in pT1–2 OSCC. And the depth cutoff at 4mm recommended by them, pertains to the population, the study has been conducted on. The presentation of these cancers varies considerably with the highest predilection seen on the tongue. These have been the most extensively studied. Tongue by virtue of its physiology and anatomic location is more prone to regional lymph node metastasis as well as skips metastasis. Whereas, in the Indian scenario, oral cancer occurs mostly due to the use of smokeless chewing tobacco. The anatomical site most commonly involved is the gingivo–buccal complex (GBC). But, a comparative evaluation of buccal mucosa and alveolus, may not agree with most of the standards observed for tongue cancers. Especially the tumor infiltration depth cut off margin, which now is considered as the most accurate predictor for future cervical lymph node metastasis. The predictive factors deciding the future cervical lymph node metastasis and recurrence in Oral Squamous Cell Carcinoma (OSCC) are of utmost importance to reduce morbidity ().

Development and validation of the Gothenburg Trismus Questionnaire (GTQ) - Corrected Proof

2012-03-14

Summary: Objectives: To develop and validate a comprehensive, self-administered questionnaire for patients with limited ability to open the mouth, trismus.Materials and methods: We derived the Gothenburg Trismus Questionnaire (GTQ) from empirical evidence in the medical literature and interviews with medical experts as well as patients. The draft version was tested in a pilot study (n=18). Patients with a maximal incisal opening (MIO) of ⩽35mm were included. The study comprised patients with benign jaw-related conditions (n=51), patients treated for head and neck (H&N) cancer (n=78) and an age- and gender-matched control group without trismus (n=129).Results: The GTQ instrument was well accepted by the patients, with satisfactory compliance and low rates of missing items. After item reduction, due to items not being conceptually relevant and/or low factor loadings, the GTQ demonstrated high internal consistency (Cronbach’s alpha 0.72–0.90), good construct validity and known-group validity.Conclusion: We developed a trismus-specific self-administered questionnaire, the GTQ, that showed good psychometric properties. We suggest this questionnaire, that has clear clinical relevance, to be adopted and used in clinical practice and in research, acting as a screening tool as well as an endpoint in intervention and jaw physiotherapy/rehabilitation studies.

Correlation of Ataxia-Telangiectasia-Mutated (ATM) gene loss with outcome in head and neck squamous cell carcinoma - Corrected Proof

2012-03-14

Summary: Objectives: Ataxia-Telangiectasia-Mutated (ATM) gene loss has been associated with poor prognosis and treatment resistance in head and neck squamous cell carcinomas (HNSCC). We investigated the relationship between ATM loss detected by fluorescence in-situ hybridisation (FISH) with patient outcome, and its relationship with Human Papillomavirus (HPV)/p16INK4A status.Material and methods: Copy number of the ATM gene and chromosome 11 were determined by FISH and HPV status was determined using p16INK4A immunohistochemistry in 87 paraffin embedded tumour samples from patients with HNSCC treated with chemoradiation at a single institution. ATM loss was correlated with patient outcome as both a continuous and dichotomous variable.Results: Of 73 evaluable patients, 44 (60.3%) demonstrated loss of the ATM gene. There was no correlation between ATM loss (defined as a mean ratio of ATM: chromosome 11<0.75) and overall survival (OS, p=0.67) or time to locoregional failure (TTLRF, p=0.72). Similarly, when evaluated as a continuous variable there was no significant relationship between ATM loss and patient outcome (OS, p=0.89; TTLRF, p=0.21). No significant relationship was found between p16INK4A status and ATM loss, for patient outcome. We found 35.6% (n=26) of patients demonstrated polysomy of chromosome 11 (defined as the presence of a mean >2.5 copies of chromosome 11) which was significantly associated with p16INK4A negative status (p=0.0004), but did not influence outcome.Conclusions: ATM loss is a frequent event in HNSCC, however it does not impact outcome after treatment with chemoradiation. Polysomy of chromosome 11 was significantly associated with p16INK4A negative status but also lacks prognostic significance.

Quality of life scores as prognostic factors of overall survival in advanced head and neck cancer: Analysis of a phase III randomized trial of pemetrexed plus cisplatin versus cisplatin monotherapy - Corrected Proof

2012-03-14

Summary: Objectives: We examined the prognostic factors (clinical, demographic, and health-related quality of life [HRQoL]) of overall survival (OS) and progression-free survival (PFS) in patients with recurrent/metastatic head and neck cancer (HNC) who were treated with pemetrexed plus cisplatin versus cisplatin in a phase III, multinational, randomized trial.Materials and Methods: Five subscales of the Functional Assessment of Cancer Therapy-Head and Neck Cancer (FACT-H&N), modified to score from 0 to 100, measured HRQoL at baseline and during treatment. Univariate and multivariate Cox proportional hazards models were used on data pooled from both treatment arms to assess the effect of baseline prognostic factors on OS and PFS.Results: Of 795 patients randomized, 704 completed a baseline FACT-H&N and were included in the analysis. Age (<65 versus ⩾65; HR=0.74, 95% CI: 0.61–0.90), race (Caucasian versus non-Caucasian; HR=0.83, 95% CI: 0.70–0.98 per table), Eastern Cooperative Oncology Group performance status (ECOG PS; 0/1 versus 2; HR=0.44, 95% CI: 0.35–0.56), prior surgery/radiotherapy in the last 6months (no versus yes; HR=0.74, 95% CI: 0.61–0.90), and primary site of disease (oral cavity versus other; HR=1.37, 95% CI: 1.15–1.63) were significantly prognostic of OS in univariate models, as were baseline scores on four FACT-H&N subscales (physical well-being, emotional well-being, functional well-being, additional concerns-H&N; HRs=0.82–0.94; all P⩽0.002). In multivariate models, significant prognostic factors were age (HR=0.78); race (HR=0.76 per table); ECOG PS (HR=0.56); prior surgery/radiotherapy (HR=0.76); and baseline scores of the FACT-H&N subscales of physical well-being, social/family well-being, and additional concerns-H&N (HRs=0.89–0.94; all P⩽0.014 per table).Conclusions: The results suggest that baseline HRQoL scores are prognostic indicators of OS in recurrent/metastatic HNC in addition to other known clinical and demographic indicators. HRQoL might be considered as a stratification factor in randomized clinical trials of recurrent/metastatic HNC.

Premetastatic vasculogenesis in oral squamous cell carcinoma xenograft-draining lymph nodes - Corrected Proof

2012-03-09

Summary: Objective: To study vascular anatomy on oral cancer-draining lymph nodes before metastasis in mice.Material and methods: Cell lines: highly lymph metastatic oral squamous cell carcinoma SASL1m and non-metastatic human adenoid cystic carcinoma ACC2. Bone marrow transplants and xenografts: Nude mice were lethally irradiated and transplanted with bone marrow cells from EGFP+ mice. SASL1m or ACC2 cells were implanted in the tongue. Non-xenografted mice were used as controls. In addition, we injected conditioned medium from SASL1m or ACC2 in transplanted mice. Immunohistochemistry: Primary tumors and neck lymph nodes were resected and stained with anti-mouse Podoplanin and CD31. Images were visualized in a confocal microscope. Image analysis: Areas covered by EGFP, CD31 and Podoplanin were measured and compared statistically. Expression microarrays: Transcriptomic microarray analysis compared SASL1 to ACC2 cells. Interactomes were generated to reveal altered pathways.Results: SASL1m cells induced the assemblage of blood vessels in cancer-free, tumor-draining lymph nodes. These blood vessels incorporated bone marrow-derived EGFP+CD31+ cells. Notably, SASL1m-conditioned medium induced a similar reaction. Non-metastatic cells failed to produce any change. Microarray and pathway analyses revealed the upregulation of Transforming Growth Factor-β, Lysyl Oxidase-like 2, Slit homolog 3 and Protease Serine 22. The upregulation of these genes was confirmed in xenografts.Conclusions: This study suggests that a blood supply for new tumors is established in lymph nodes before metastasis. It also suggests that premetastatic vasculogenesis and primary tumor angiogenesis may be mediated by different mechanisms.