Oral Oncology - Articles in Press

Evaluation of speech outcomes using English version of the Speech Handicap Index in a cohort of head and neck cancer patients - Corrected Proof

2012-01-30

Summary: The aim of this study was to explore post-treatment speech impairments using English version of Speech Handicap Index (SHI) (first speech-specific questionnaire) in a cohort of oral cavity (OC) and oropharyngeal (OP) cancer patients. Sixty-three consecutive OC and OP cancer patients in follow-up participated in this study. Descriptive analyses have been presented as percentages, while Mann–Whitney U-test and Kruskall–Wallis test have been used for the quantitative variables. Statistical Package for Social Science-15 statistical software (SPSS Inc., Chicago, IL) was used for the statistical analyses. Over a third (36.1%) of patients reported their speech as either average or bad. Speech intelligibility and articulation were the main speech concerns for 58.8% and 52.9% OC and 31.6% and 34.2% OP cancer patients, respectively. While feeling of incompetent and being less outgoing were the speech-related psychosocial concerns for 64.7% and 23.5% OC and 15.8% and 18.4% OP cancer patients, respectively. Worse speech outcomes were noted for oral tongue and base of tongue cancers vs. tonsillar cancers, mean (SD) values were 56.7 (31.3) and 52.0 (38.4) vs. 10.9 (14.8) (P<0.001) and late vs. early T stage cancers 65.0 (29.9) vs. 29.3 (32.7) (P<0.005). The English version of the SHI is a reliable, valid and useful tool for the evaluation of speech in HNC patients. Over one-third of OC and OP cancer patients reported speech problems in their day-do-day life. Advanced T-stage tumors affecting the oral tongue or base of tongue are particularly associated with poor speech outcomes.

Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients - Corrected Proof

2012-01-30

Summary: Recently, apelin has been shown to be a novel angiogenic factor in various cancers including lung, breast and brain cancer. However, there is limited information regarding the expression and role of apelin in oral cavity cancer. In this study, we determined that apelin expression was localized in the cytoplasm of oral squamous cell carcinoma at various intensities. Strong apelin expression significantly correlated with tumor recurrence and disease-free survival. Using a multivariate analysis, we demonstrated that apelin was an independent prognostic factor for on disease-free survival, age, lymph node metastasis and CA9 expression. Moreover, apelin expression was up-regulated under hypoxic conditions, and exogenous apelin enhanced the proliferation and migration of oral cancer cells. Based on these results, we propose that the presence of hypoxia-induced apelin is a new prognostic factor and potential therapeutic target for oral squamous cell carcinoma.

mTOR expression and prognosis in elderly patients with laryngeal carcinoma: Uni- and multivariate analyses - Corrected Proof

2012-01-30

Summary: Cancer is common in the elderly, who may also be frail, which can complicate the choice of the best therapeutic approach. We sought to examine whether the serine–threonine kinase mTOR, a “master switch” in cancer cells that modulates metabolism, the cell cycle, and apoptosis, might help in clinical decision-making. The aim of the present study was thus to assess the potential prognostic role of mTOR in elderly patients with laryngeal carcinoma (LSCC). mTOR expression was determined immunohistochemically in 54 consecutive elderly (⩾65years old) patients with LSCC. On univariate analysis, nodal involvement and pathological stage correlated strongly with the elderly LSCC patients’ prognosis in terms of disease recurrence rate and disease-free survival (DFS). Patients whose mTOR expression was >35.3% had a significantly higher recurrence rate (p=0.003) and shorter DFS (p=0.013). In the multivariate model, N status (p=0.001) and mTOR expression (p=0.026) maintained an independent prognostic significance in relation to DFS. mTOR probably influences the aggressive LSCC phenotype in elderly patients and its expression in elderly LSCC cases can be considered a prognostic marker potentially useful for identifying patients at higher risk of disease recurrence, and N0 patients at higher risk of recurrence who may benefit from more aggressive treatment. Since rapalogs (as mTOR inhibitors) might have an effect on LSCC, further investigations are needed to ascertain these agents’ role in therapeutic strategies for advanced LSCC in elderly patients.

Comparison of the NCI-CTCAE version 4.0 and version 3.0 in assessing chemoradiation-induced oral mucositis for locally advanced nasopharyngeal carcinoma - Corrected Proof

Yu-Jie Liu, Guo-Pei Zhu, Xi-Yin Guan — 2012-01-30

Summary: To compare the role of CTCAE version 4.0 (v4.0) and version 3.0 (v3.0) in assessing chemoradiation-induced oral mucositis (OM) for locally advanced nasopharyngeal carcinoma (LA-NPC). Patients with LA-NPC were recruited into the study. All eligible participants received docetaxel and cisplatin-based induction chemotherapy followed by intensity modulated radiation therapy concurrent with cisplatin. OM was assessed before and weekly during radiotherapy (RT), using CTCAE v3.0 (clinical exam) and v4.0 separately. OM-related quality of life (QOL) was also evaluated in these patients with the EORTC Quality of Life Questionnaire – Head and Neck module (QLQ-H&N35). From June 2010 to February 2011, 23 eligible patients were enrolled. A highly significant correlation (rho=0.838, p=0.000) and a non-significant difference (p=0.167) in OM grades were found between the two CTCAE versions. However, the trend lines showed that the mean grade determined by CTCAE v3.0 reached a plateau while the mean grade determined by v4.0 continued to increase after the fourth week during RT. Changing trends of several QOL subscale mean scores were similar to that of OM mean grade evaluated by CTCAE v4.0. Both grades of the two CTCAE versions were significantly and positively correlated with scores of several QOL subscales. Nonetheless, the correlation coefficients related to CTCAE v4.0 were higher than those related to v3.0 (rho: 0.727–0.865 versus 0.727–0.778). CTCAE v4.0 could serve as a good surrogate for v3.0 (clinical exam) in assessing chemoradiation-induced oral mucositis. Moreover, CTCAE v4.0 has a few subtle advantages over v3.0 under some circumstances such as delegating QOL. However, there is still no “gold standard” assessment scale for oral mucositis. Therefore, the appropriate tool should be carefully chosen according to the purpose of assessment.

Comment on the article “Proposed clinical classification for oral submucous fibrosis” by Chandramani B. More et al. - Corrected Proof

Richa, Niharika Swain, Vibha, Jay Gopal Ray, Sripati Rao — 2012-01-25

We would like to comment on the article “Proposed clinical classification for oral submucous fibrosis” by Chandramani B. More et al. We appreciate the extensive work up by authors on 4000 cases of oral submucous fibrosis. On the basis of previous literature on the disease and our institutional experience, we would like to further stress on certain issues as following:

HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer - Corrected Proof

2012-01-24

Summary: HMGB1 has gained a prominent role in cancer development and is implicated in tumor escape phenomena. To date, only few data are available on effects of HMGB1 on regulatory T cells (Treg) in cancer patients. This study evaluates the prevalence of HMGB1 and its effects on Treg in patients with head and neck squamous cell carcinoma (HNSCC). Sixty-seven patients with HNSCC and seventeen healthy donors were included in this study. Tumor tissues of patients were analyzed for expression of HMGB1 employing immunofluorescence and qRT-PCR. HMGB1 serum levels were assessed using ELISA. Tumor-infiltration and Treg from peripheral blood were phenotyped with flow cytometry and immunofluorescence microscopy. Migration and suppressive function of Treg upon HMGB1 stimulation was analyzed in chemotaxis assays and CFSE assays. HMGB1 is overexpressed in tumor cells of HNSCC, and serum levels are significantly elevated. Tumor-infiltrating Treg express HMGB1-recognizing receptors, TLR4 and RAGE. HMGB1 is a chemoattractant for Treg and promotes their suppressive function. Our data provide new aspects how the HMGB1 tumor-derived danger signal augments function of Treg in patients with HNSCC.

Characterization of bone resorption in novel in vitro and in vivo models of oral squamous cell carcinoma - Corrected Proof

2012-01-24

Summary: Oral squamous cell carcinoma (OSCC) is the most commonly diagnosed oral malignancy in humans and cats and frequently invades bone. The objective of this study was to determine if feline OSCC serves as a relevant model of human OSCC in terms of osteolytic behavior and expression of bone resorption agonists. Novel feline OSCC cell lines (SCCF2 and SCCF3) were derived from spontaneous carcinomas. Gene expression and osteolytic behavior were compared to an established feline OSCC cell line (SCCF1) and three human OSCC cell lines (UMSCC-12, A253 and SCC25). Interaction of OSCC with bone and murine pre-osteoblasts (MC3T3) was investigated using in vitro co-culture techniques. In vivo bioluminescent imaging, Faxitron radiography and microscopy were used to measure xenograft growth and bone invasion in nude mice. Human and feline OSCC expressing the highest levels of parathyroid hormone-related protein (PTHrP) were associated with in vitro and in vivo bone resorption and osteoclastogenesis. MC3T3 cells had increased receptor activator of nuclear factor κB ligand (RANKL) expression and reduced osteoprotegerin (OPG) expression in conditioned medium from bone-invasive SCCF2 cells compared to minimally bone invasive SCCF3 cells, which was partially reversed with a neutralizing anti-PTHrP antibody. Human and feline OSCC cells cultured in bone-conditioned medium had increased PTHrP secretion and proliferation. Feline OSCC-induced bone resorption was associated with tumor cell secretion of PTHrP and with increased RANKL:OPG expression ratio in mouse preosteoblasts. Bone-CM increased OSCC proliferation and secretion of PTHrP. The preclinical models of feline OSCC recapitulated the bone-invasive phenotype characteristic of spontaneous OSCC and will be useful to future preclinical and mechanistic studies of bone invasive behavior.

Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: A report of 32 cases - Corrected Proof

Marco Mozzati, Giorgia Gallesio, Valentina Arata, Renato Pol, Matteo Scoletta — 2012-01-20

Summary: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an important complication in cancer patients taking intravenous BPs (BPs). In most cases, BRONJ is associated with an oral surgery procedure involving jaw bone. Currently, BRONJ management remains controversial, and there is no definitive standard of care for this disease. In fact, several articles in the recent literature discuss treatments that range from topical to surgical treatment, without definitive conclusion about treatment. A clinical study was conducted on 32 patients treated with i.v BPs for oncologic pathologies affected by BRONJ. The patients were treated by resection of the necrotic bone with primary closure of the mucosa over the bony defect using plasma rich in growth factors (PRGF). Orthopanoramic and computed tomography were performed before and after surgery. No intraoperative complications were observed, and all 32 cases were treated successfully. Our data on the use of PRGF demonstrate positive results for this surgical treatment. PRGF may enhance vascularization and regeneration of osseous and epithelial tissues.

Transoral robotic surgery for hypopharyngeal squamous cell carcinoma: 3-Year oncologic and functional analysis - Corrected Proof

2012-01-20

Summary: The recent trend in treatment of hypopharyngeal cancer is organ preservation in order to maintain swallowing and speech function as well as improve quality of life. Transoral robotic surgery (TORS) can remove hypopharyngeal lesions successfully without an external incision, preserving physiologic functions of affected organs. However, studies have yet to assess the oncologic and functional results of TORS for the treatment of hypopharyngeal cancer. This prospective study evaluated the oncologic and functional results of TORS for the treatment of hypopharyngeal cancer obtained at our institution over a period of 3years and confirmed the validity of TORS as a surgical organ-preserving strategy. Between April 2008 and September 2011, 23 patients who were diagnosed with hypopharyngeal cancer underwent TORS for removal of a primary lesion. The da Vinci Robotic system (Intuitive Surgical Inc., Sunnyvale, California) was used to remove the lesion. The Kaplan–Meier method was used to analyze overall survival and disease-free survival. Videopharyngogram study (VEF) was performed and functional outcome swallowing scale (FOSS) was utilized to measure and evaluate swallowing function. Acoustic wave form analysis was conducted to evaluate voice status. Overall survival at 3years was 89% and disease-free survival was 84%. On the VEF study, serious aspiration or delay of swallowing was not observed during the pharyngeal stage of the swallowing process. Overall, 96% of the patients showed favorable swallowing abilities with an FOSS score ranging from 0 to 2. The fundamental frequency variation (vF0) and jitter were increased upon acoustic waveform analysis (vF0=2.71±0.063, Jitter=2.01±0.034), but the harmonic-to-noise ratio (HNR) and shimmer were maintained close to the normal range (HNR=1.28±0.001, Shim=1.74±0.036). The oncologic and functional results of TORS were quite acceptable for the treatment of hypopharyngeal cancer. TORS is a valid treatment option as a surgical, organ-preserving strategy for select patients with hypopharyngeal cancer.

International incidence of oropharyngeal cancer: A population-based study - Corrected Proof

Marianna de Camargo Cancela, Dyego Leandro Bezerra de Souza, Maria Paula Curado — 2012-01-20

Summary: The incidence of oropharyngeal cancer is not well documented as it is rarely described according to the anatomic definition but usually grouped with oral cavity subsites. The aim of this study was to calculate oropharyngeal cancer incidence and compare it to oral cavity cancer incidence. Age-standardized incidence rates (ASR) of oropharyngeal cancer were calculated for the period between 1998 and 2002, based on data from Cancer Incidence in 5 Continents, Volume IX (CI5-IX). These ASRs were compared with previously published oral cavity cancer data. Among males, the highest ASRs were observed in France, Slovakia, Slovenia and Brazil. The highest oral cavity/oropharyngeal cancer rate ratio was observed in Pakistan, among males (6.2) and females (13.5). The results provide an overview of oropharyngeal cancer incidence and constitute a basis for the development of primary and secondary prevention, according to geographical variations and topography.

Primary malignant melanoma, of head and neck: A comprehensive review of literature - Corrected Proof

A.K. Vikey, Deepali Vikey — 2012-01-20

Summary: Malignant melanoma; since long time is considered as deadly disease, but risk factor is minimized due to new technologies, substantial literatures, and promising treatments. The diverse etiopathogenesis; including physical carcinogens, bio-molecules, biological behavior, anatomical locations, and negligence; contribute to complexity of disease. So even after advanced medical technology, malignant melanoma is the challenge to doctors as well as common public. There is increase in incidence rate day by day, which directly attributes to recent concept of sun beds or tanning beds and global climate. After considering its severity, different researches are carried out in the field of radiology and biotechnology. But again these are not sufficient to control the disease. However; to reduce the mortality there is need of general public awareness regarding causative factors and preventive measures. Many literatures recently advocate for long time survival of malignant melanoma, after its early detection and treatment.

Long-term treatment outcome of minor salivary gland carcinoma of the hard palate - Corrected Proof

2012-01-16

Summary: Minor salivary gland carcinoma of the hard palate is rare, and its long-term survival rate is high, making it difficult to evaluate the prognostic factors and the efficacy of treatment. This study was designed to evaluate the treatment outcome of minor salivary gland carcinoma of the hard palate. 103 cases of minor salivary gland carcinoma of the hard palate treated with surgery alone or underwent surgery combined with post-operative radiotherapy hospitalized in Cancer Center, Sun Yet-Sen University, from 1968 to 2008 were reviewed retrospectively. The most common histologic types were adenoid cystic carcinoma in 48 patients(46.6%), mucoepidermoid carcinoma in 37(35.92%), malignant mixed tumor in 15(14.56%), and acinic cell carcinoma in 3(2.91%). The median follow-up time was 74.83months (range 0.9–356.57months). Overall outcomes at 5 and 10years were overall survival (OS), 77.9% and 65.7%; recurrence-free survival (RFS), 64.4% and 53.2%; and disease specific survival (DSS), 77.9% and 67.7%, respectively. There was no significant difference in overall survival (P=0.52), recurrence-free survival (P=0.762) and disease specific survival (P=0.449) between patients who underwent surgery alone and those who underwent surgery plus post-operative radiotherapy. Surgery has been accepted as the primary treatment for minor salivary gland carcinoma of hard palate. Sufficient surgical excision with adequate margins is essential for a favorable outcome. We advocate using radiotherapy in the post-operative context for patients with poorly differentiated, cervical lymph node metastasis, positive or close margins, and large primary lesions.

Increased serum placenta growth factor level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma - Corrected Proof

2012-01-16

Summary: We recently found that the expression of placenta growth factor (PlGF) in oral squamous cell carcinoma (OSCC) specimens is correlated with the progression and prognosis of OSCC. In this study, serum samples were obtained from 72 OSCC patients before and 3months after surgical cancer excision and from 30 normal controls. Serum PlGF levels were determined by enzyme-linked immunosorbent assay (ELISA). The mean serum PlGF levels were significantly higher in pre-surgery OSCC patients than in normal controls (19.1±10.7 vs. 10.1±4.5, P<0.001). Serum PlGF levels dropped to near the normal control levels after surgical cancer removal. Higher pre-surgery serum PlGF levels were significantly associated with larger tumor size (P=0.015), positive lymph node metastasis (P=0.001), more advanced clinical stages (P=0.002), and loco-regional recurrence (P=0.037). The serum PlGF level was identified as an independent unfavorable prognosis factor by multivariate Cox regression analyses (P=0.014). Kaplan–Meier curve showed that OSCC patients with a higher serum PlGF level had a significantly poorer cumulative recurrence-free survival than those with a lower serum PlGF level (log-rank test, P=0.009). When we used the serum PlGF level of 19.1pg/ml (mean normal control value plus 2 standard deviations) as a cutoff point, the sensitivity, specificity, and positive predictive value for tumor recurrence was 80%, 56% and 78%, respectively. We conclude that the serum PlGF level may be a valuable biomarker for prediction of therapeutic effect, progression, recurrence and prognosis of OSCC.

Ras oncogenes in oral cancer: The past 20 years - Corrected Proof

Avaniyapuram Kannan Murugan, Arasambattu Kannan Munirajan, Nobuo Tsuchida — 2012-01-12

Summary: Oral squamous cell carcinoma (OSCC) of head and neck is associated with high morbidity and mortality in both Western and Asian countries. Several risk factors for the development of oral cancer are very well established, including tobacco chewing, betel quid, smoking, alcohol drinking and human papilloma virus (HPV) infection. Apart from these risk factors, many genetic factors such as oncogenes, tumor suppressor genes and regulatory genes are identified to involve in oral carcinogenesis with these risk factors dependent and independent manner. Ras is one of the most frequently genetically deregulated oncogene in oral cancer. In this review, we analyze the past 22years of literature on genetic alterations such as mutations and amplifications of the isoforms of the ras oncogene in oral cancer. Further, we addressed the isoform-specific role of the ras in oral carcinogenesis. We also discussed how targeting the Akt and MEK, downstream effectors of the PI3K/Akt and MAPK pathways, respectively, would probably pave the possible molecular therapeutic target for the ras driven tumorigenesis in oral cancer. Analysis of these ras isoforms may critically enlighten specific role of a particular ras isoform in oral carcinogenesis, enhance prognosis and pave the way for isoform-specific molecular targeted therapy in OSCC.

Electron beam radiotherapy for tongue cancer using an intra-oral cone - Corrected Proof

2012-01-12

Summary: To explain the adaptation technique using an intra-oral cone (IOC) for radiation therapy, and to determine the optimal schedule resulting in a high local control rate and an acceptable complication rate using direct electron beam radiation for the treatment of tongue cancer. Thirty patients with the tongue cancer (T1:T2:T3=16:11:3) were treated with 6–15MeV electron radiation using an IOC. Twenty-six patients were treated with electron radiation using an IOC with or without an excisional biopsy. The other four patients were treated with a combination of the external beam radiation and electron radiation using the IOC. In order to formulate a safe and effective treatment program, we calculated the biologically effective dose (BED). The two- and five-year local control rates for all patients were 63% and 52%, respectively. The two- and five-year overall survival rates for all patients were 73% and 69%, respectively. Local control was achieved in 12 of 15 patients who were irradiated with a BED of 90.9Gy10 or more, whereas it was not achieved in nine of the 15 patients who were treated with less than a BED of 90.9Gy10 (p=0.03). The application of electron radiation using an IOC for the treatment of tongue cancer provides acceptable local control and adverse effect rates, especially for elderly patients considered to be high risk for complications from anesthesia. The optimum BED10 value for the treatment of early tongue cancer using the IOC technique appears to be at least 90.9Gy10.

Diagnostic value of CT and MRI in the detection of paratracheal lymph node metastasis - Corrected Proof

2012-01-06

Summary: The presence of paratracheal lymph node (PTLN) metastasis harbours a worse prognosis. Uniform guidelines on PTLN dissection are missing, mainly because of the value of diagnostic techniques for the detection of PTLN metastasis are not clear. This study is performed to identify CT and MRI criteria for detection of PTLN metastasis. 149 patients who underwent laryngectomy and a PTLN dissection between 1990 and 2010 were included. Patient, tumour, treatment and follow up data were collected. On computed tomography (CT) and magnetic resonance imaging (MRI) different test criteria were examined. Considering PTLN with a maximal axial diameter of ⩾5mm as positive predicts PTLN metastasis best: sensitivity and specificity 70% and 36% (CT) and 50% and 71% (MRI). Other risk factors for PTLN metastasis were subglottic extension of the tumour (sensitivity is 45%) and clinical positive neck status (sensitivity is 59%). When atleast one of these risk factors was present and the status of PTLN was considered positive, a high sensitivity (90% for CT and 100% for MRI) and a lower specificity (19% for CT and 32% for MRI) was found. If atleast one of the risk factors such as subglottic extension, clinical positive neck and PTLN with a maximal axial diameter of ⩾5mm is present, sensitivity and negative predictive value for the prediction of PTLN metastasis are high, but the specificity is low. These risk factors can be used to select laryngectomy patients for PTLN dissection.

Treatment outcomes and prognostic features in adenoid cystic carcinoma originated from the head and neck - Corrected Proof

Chunying Shen, Tingting Xu, Caiping Huang, Chaosu Hu, Shaoqin He — 2012-01-03

Summary: Surgery is the main treatment modality for adenoid cystic carcinoma (ACC) originated from the head and neck. However, the extensive local infiltrative and perineural spread related to this malignancy often cause difficulty to achieve high tumor control. The aim of this study is to evaluate the efficacy of postoperative radiotherapy (RT) in ACC, and to identify prognostic variables associated with treatment outcomes. A retrospective review of 101 patients diagnosed with ACC in the head and neck region was performed. T stage distribution was T1, 25; T2, 35; T3, 18; and T4, 23 patients. All patients were grouped into two arms: surgery alone or combined with postoperative radiotherapy. The 5-year local–regional control (LRC), overall survival (OS) and disease-free survival (DFS) rates for all the patients were 70.5%, 91.7% and 63.2%, respectively. On univariant analysis, postoperative radiotherapy did improve the 5-year LRC and DFS compared to surgery alone (81.0% vs. 53.4%, p=0.0003 and 71.3% vs. 50.0%, p=0.0052, respectively). And patients with T1–T2 lesions achieved better treatment outcomes, whereas stage T3–T4 was associated with high local failure and poor disease-free survival. Furthermore, multivariate analysis revealed that the addition of radiotherapy and early lesions were both favorite predictors for local control and survival rates. The prognosis for ACC of the head and neck was excellent. Surgery combined with postoperative radiotherapy significantly reduced the local failure, and further improved disease-free survival. Nevertheless, the relatively high distant metastasis was an obstacle of curing the ACC patients.

Enteral feeding outcomes after chemoradiotherapy for oropharynx cancer: A role for a prophylactic gastrostomy? - Corrected Proof

2011-12-30

Summary: To determine the outcomes of patients managed with different routes of enteral feeding during chemoradiotherapy for oropharynx cancer. The hospital and dietetic records of consecutive patients with oropharynx squamous cell carcinoma treated between January 2007 and June 2009 with concurrent chemoradiotherapy were reviewed retrospectively. One hundred and four patients were analysed. Seventy-one received a prophylactic gastrostomy, 21 were managed with a strategy of NG tube as required and 12 received a therapeutic gastrostomy. Patients with a prophylactic gastrostomy commenced enteral feeding a median of 24days after commencing radiotherapy, compared with a median of 41days (p<0.001) for the NG as required group. Comparing prophylactic gastrostomy, NG as required and therapeutic gastrostomy, median number of unplanned inpatient days were 6, 14 and 7, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Mean percentage weight loss at the end of treatment (6.1% vs. 7.1% vs. 5.2%, respectively) and at 6months post-radiotherapy (11.7%, 14.3% and 8.9%) were similar in all groups (p=0.23). There was no significant difference in type of diet post-radiotherapy between prophylactic gastrostomy and NG as required groups (p=0.22). Median duration of enteral feeding was 181, 64 and 644days, respectively (p<0.01 for prophylactic gastrostomy vs. NG as required). Use of a prophylactic gastrostomy (p<0.01) and higher T stage (p<0.01) were associated with increased duration of enteral feeding on a multivariate analysis. These data reinforce concerns regarding the detrimental impact of prophylactic gastrostomy placement upon long-term enteral feed dependence.

Review of drug treatment of oral submucous fibrosis - Corrected Proof

2011-12-29

Summary: This study undertook a review of the literature on drug treatment of oral submucous fibrosis. An electronic search was carried out for articles published between January 1960 to November 2011. Studies with high level of evidence were included. The levels of evidence of the articles were classified after the guidelines of the Oxford Centre for Evidence-Based Medicine. The main outcome measures used were improvement in oral ulceration, burning sensation, blanching and trismus. Only 13 publications showed a high level of evidence (3 randomized controlled trials and 10 clinical trials/controlled clinical trials), with a total of 1157 patients. Drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene, have been used. Only systemic agents were associated with few adverse effects like gastritis, gastric irritation and peripheral flushing with pentoxifylline, and flushingly warm skin with nylidrin hydrochloride; all other side-effects were mild and mainly local. Few studies with high levels of evidence were found. The drug treatment that is currently available for oral submucous fibrosis is clearly inadequate. There is a need for high-quality randomized controlled trials with carefully selected and standardized outcome measures.

A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nanopharyngeal carcinoma - Corrected Proof

T.K. Yau, T. Shum, A.W.M. Lee, M.W. Yeung, W.T. Ng, L. Chan — 2011-12-29

Summary: Pemetrexed is a novel chemotherapy agent with good efficacy and toxicity profiles. This phase II study aimed at evaluating its use in combination with cisplatin for recurrent or metastatic nasopharyngeal carcinoma (NPC). All participating patients had metastatic or recurrent NPC with prior treatment by platinum-based chemotherapy. The study regimen comprised of pemetrexed 500mg/m2 and cisplatin 75mg/m2, repeated 3-weekly for 4 cycles. Efficacy evaluation was based on both radiological and biochemical responses. Patients with no progressive disease and good tolerance were given another 2–4 cycles. Fifteen patients were treated for a total of 4–8 cycles (median, 6 cycles); 9 had distant metastases and 6 had loco-regional recurrences only. Reduction of DNA copies of EB virus by ⩾50% was observed in 93% accessible patients, with 21% of them being biochemical complete response (CR). Radiologically, 1 (7%) patient achieved CR, 2 (13%) achieved partial response and 8 (53%) had stable diseases. The median time to progression was 30weeks. Treatment was well tolerated with only 1 (7%) patient developing grade 4 toxicity (of anemia). The most common grade 3 toxicities were neutropenia (27%) and anemia (20%). The baseline mean total QOL scores (as measured with FACT-H&N version 4) was 100.4 and showed no significant change after the fourth cycle (95.6, p=0.20) and sixth cycle (91.9, p=0.15). Pemetrexed in combination with cisplatin is a well tolerated regimen with encouraging efficacy for metastatic and recurrent NPC. Further evaluation of its role in the management of NPC is warranted.

Clinical significance of lymphatic and blood vessel invasion in oral tongue squamous cell carcinomas - Corrected Proof

2011-12-19

Summary: Although vascular invasion (VI) is recognized as an important predictor of lymph node metastasis and a significant prognostic factor in head and neck squamous cell carcinoma (HNSCC), there is currently no common definition for the pathological evaluation of VI status. We reviewed the medical records of 63 consecutive resected primary oral tongue SCCs (OTSCCs) without preoperative treatment between June 1999 and April 2008, and evaluated VI status by investigating lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) by using immunohistochemistry (IHC) with monoclonal antibody D2-40 (D2-40) and Elastica van Gieson (EVG) staining, respectively. Subsequently, we analyzed their correlations with cervical lymph node metastasis and prognosis. LVI was found in 16 of the 63 tumors (25.4%) and BVI was in 32 tumors (50.8%). Univariate analysis revealed that the presence of LVI is statistically correlated with lymph node metastasis. Moreover, multivariate logistic regression analysis revealed that LVI is an independent risk factor of nodal metastasis (odds ratio=4.262, 95% confidence interval=1.262–14.397, p=0.020). In contrast, Kaplan–Meier survival analysis revealed that patients with BVI had a significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those without BVI (68.6% versus 90.3%, p=0.028 and 68.6% versus 93.5%, p=0.013, respectively). The present study clearly demonstrated that LVI at primary OTSCC had significant correlation with lymph node metastasis, and that BVI was significantly associated with recurrence and poor prognosis. Evaluation of VI status, as LVI and BVI status separately, using IHC with D2-40 and EVG staining may be useful in predicting lymph node metastasis and poor prognosis in OTSCCs.

The prognostic value of histological typing in nasopharyngeal carcinoma - Corrected Proof

Florence Cheung, Oscar Chan, Wai Tong Ng, Lucy Chan, Anne Lee, Siu Wah Pang — 2011-12-19

Summary: We analyzed the relation of histological typing in late stage nasopharyngeal carcinoma (NPC) with clinical outcome and excision repair cross complementation group 1 protein (ERCC1) expression. The biopsy specimens of 259 patients with NPC were reviewed by two pathologists for classification according to 2005 WHO subtypes. The patients were of stage III to IVB and treated with radiotherapy (RT) alone or concurrent–adjuvant chemoradiotherapy (CRT). Expression of ERCC1 protein detected by immunohistochemistry on paraffin sections was correlated with the histological subtypes. There were 10 cases (3.9%) of differentiated non-keratinizing carcinoma compared with 249 cases of conventional undifferentiated carcinoma. The former exhibited more advanced squamous differentiation with 3 cases belonging to the papillary variant. The degree of ERCC1 expression was generally high compared with the median of the cohort. Clinically, the differentiated group fared poorly compared with the undifferentiated group with respect to loco-regional failure-free rate, distant failure-free rate, disease-free survival and overall survival (p⩽0.05). Treatment modality of the 10 patients (5 RT, 5 CRT) was similar to the whole cohort. Contrary to general acceptance that differentiation of non-keratinizing NPC had little bearing on prognosis, we demonstrated that in endemic area differentiation in fact conferred a worse prognosis in stage III to IVB patients. There was positive correlation of differentiation with ERCC1 expression. We advocate precise histological typing of NPC in pathology report for prognostic purpose and outcome correlation.

Early detection of oral cancer: Detector lies within - Corrected Proof

Sachin C. Sarode, Gargi S. Sarode, Swarada Karmarkar — 2011-12-19

It is an eminent fact that the prognosis of patients with OSCC is largely influenced by the stage of the disease at the time of diagnosis. Unfortunately, almost half of the patients with OSCC worldwide are diagnosed at advanced stages (III, IV) with five year survival rates ranging from 20% to 50% depending on the tumor site. Thus, early diagnosis (at stages I/II) and referral is the key to a better prognosis, reducing the mortality from the disease. Also, if detected early, one can take benefit of the advanced techniques, for example, intraoral ultrasonography for measuring the tumor thickness, CT scan, MRI etc. to predict lymph node metastasis in patients with stage I/II OSCC. These techniques could be immensely helpful for deciding the correct and conservative treatment approach for stage I/II OSCC avoiding unnecessary mutilating interventions. But unfortunately, we are not able to take such advantage of these available opportunities because of late presentation/diagnosis in advanced stage of OSCC as mentioned earlier (Patient related diagnostic delay=appraisal delay+illness delay+utilization delay).

Association between the rs2910164 polymorphism in pre-mir-146a and oral carcinoma progression - Corrected Proof

2011-12-19

Summary: MicroRNAs are short non-coding RNAs that regulate gene expression by RNA interference. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. miR-146a has been reported to regulate Toll-like receptors and cytokine signaling, which are both crucial for inflammation and oncogenesis. This study identifies that areca nut extract, TNFα and TGFβ up-regulates miR-146a in OSCC cells. The increased expression of miR-146a enhanced the oncogenicity of OSCC cells. In addition, a G to C polymorphism (rs2910164), which is located in the pre-miR-146a and has been associated with functional alterations in miR-146a, was significantly more prevalent among OSCC patients having more advanced nodal involvement. Our analysis also suggested a higher miR-146a expression in OSCC tissues of patients carrying C polymorphism. The present study concluded a higher prevalence of the pre-mir-146a C-variant was associated with OSCC progression in patients with this disease.

Transfusion of allogenic leukocyte-depleted packed red blood cells is associated with postoperative morbidity in patients undergoing oral and oropharyngeal cancer surgery - Corrected Proof

2011-12-19

Summary: 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 1–4units transfused: adjusted OR, 2.59; 95% CI, 1.24–5.39; p=0.011; for more than >4units 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.

Tumor-associated carbonic anhydrase XII is linked to the growth of primary oral squamous cell carcinoma and its poor prognosis - Corrected Proof

2011-12-15

Summary: The pattern of protein expression in tumors is under the influence of nutrient stress, hypoxia, and low pH, which determines the survival of neoplastic cells and the development of tumors. Carbonic anhydrase (CA) XII is a transmembrane enzyme that catalyzes the reversible hydration of cell-generated carbon dioxide into protons and bicarbonate. Hypoxic conditions activate its transcription and translation, and enhanced expression is often present in several types of tumors. However, CA XII expression in oral squamous cell carcinoma (OSCC) and its correlation with patients’ prognosis have not been investigated so far. In this study, we detected the expression of CA XII in 264 patients with OSCC using tissue microarrays (TMAs), and evaluated its correlation with clinicopathologic factors and disease prognosis. CA XII expression was present in 185/264 (70%) cases and was associated with more-advanced clinical stages (p=0.003), a larger tumor size (p<0.001), and postoperative recurrence (p=0.047), but was not associated with positive lymph node metastasis or distal metastasis. Importantly, CA XII expression was correlated with a poorer patient prognosis in a univariate (p=0.034, log-rank test) survival analysis. According to our results, the expression of CA XII in OSCC samples can predict the progression of OSCC and survival of OSCC patients.

CT-scan is a valuable tool to detect mandibular involvement in oral cancer patients - Corrected Proof

2011-12-12

Summary: In patients with oral squamous cell carcinomas (OSSC) it is desirable to avoid unnecessary bone resection without neglecting the overall surgical treatment goal of tumor-free margins. Whereas computed tomography (CT) is most commonly used to detect mandibular invasion, there are conflicting reports regarding the accuracy of CT. Therefore, the aim of this study was to reinvestigate the accuracy of CT in predicting mandibular involvement by OSSC. One hundred and seven patients with OSSC who received a mandibulectomy were included. Before treatment all patients underwent a contrast-enhanced multi-detector CT. Axial 3 or 1.25mm thick images were reconstructed for evaluation in overlapping technique and displayed in a bone (1400/400HU) and a soft tissue window (350/50HU). CT scans were examined by three investigators and compared with the histological findings. The radiological examination showed a high interrater reliability (Cronbachs alpha 0.982). Comparing the radiological findings with the histological results the CT showed 8 false-positive results and 8 false-negative patients. The quality criteria for detecting bone involvement of OSSC by CT were calculated as follows: sensitivity 82.6%; specificity 86.9%; positive predictive value 82.6%; negative predictive value 86.9%. However, in all false-positive patients a sagittal bone defect of 15.1mm could be found presumably caused by pressure of the tumor, but no histologically detectable bone infiltration. Modern CT (1–2mm sections) is a valuable tool for surgical treatment planning. If bone invasion is detected, a mandibulectomy seems always reasonable. In radiologically negative cases histological assessment is necessary to detect mandibular involvement.

Influence of irradiation and oncologic surgery on head and neck microsurgical reconstructions - Corrected Proof

2011-12-12

Summary: Despite the refinement of microsurgical techniques, microsurgical free flap transfer in patients with a history of previous radiotherapy, neck dissection or free flaps remains a challenge in oncologic reconstructive surgery. Previous studies on the prognostic factors for postoperative complications have been largely retrospective and shown conflicting results. Our aim was to design a prospective study to identify negative outcome predictors of free flap surgery in previously treated oral cancer patients. Prospective study including all patients who required microsurgical free flap transfer for reconstruction of the oral cavity between July of 2007 and June of 2010 with subset analysis of those cases in whom previous surgical or nonsurgical oncological treatment for head and neck cancer had been carried out. A total of 360 free flaps were performed in 358 patients, of whom 61 had previous neck dissection and 58 had undergone radiation therapy. Operation time was significantly found to be longer in irradiated patients. The need for microsurgical revision, postoperative wound infection and free flap loss were significantly associated with the ASA score and a previous neck dissection. Wound infection was seen significantly more often after radiotherapy. Previous neck dissections and radiotherapy as well as the ASA score are significant negative predictors for success in free flap transfer. For patients with prior oncologic treatments in their medical history, we recommend detailed preoperative assessment of the vascular status and an intensified postoperative care to reduce complication rates to improve outcome in oncologic reconstructive surgery.

Prediction model for early percutaneous endoscopic gastrostomy (PEG) in head and neck cancer treatment - Corrected Proof

K. Wermker, S. Jung, L. Hüppmeier, U. Joos, J. Kleinheinz — 2011-12-09

Summary: Head and neck cancer patients are prone to nutritional problems, partly due to the location and size of the disease, due to significant comorbidity and also often therapeutic intervention. Excessive weight loss after surgery reduces further the patients’ physical resistibility and increases the complication rate for adjuvant radiation and or chemotherapy. Possible effective interventions are dietary counseling, nutritional supplements or drug interventions. Aim of our research was to reveal reliable clinical predictive parameters, which calculate risks as the reduced nutritional state against the possible complications of PEG insertion and finally define an algorithm for pre-therapeutic PEG insertion to optimize the general treatment conditions by sufficient nutrition. We explored the data of 152 patients in a time period from 2005 to 2010 considering age, gender, body mass index, staging, size and localization of the tumor or need for a neck dissection. The decisive predictive parameters are: body mass index, size and localization of tumor, lymph node affection, resection of the root of the tongue or the oropharynx region and performance of a neck dissection. In this retrospective study we established a prediction model that allows a substantiated evaluation of post-therapeutic dysphagia considering relevant clinical features as well as the specific surgical therapy. From this assessment derives the indication of a safe pre-therapeutic application of a percutaneous endoscopic gastrostomy (PEG).

The Bozola flap in oral cavity reconstruction - Corrected Proof

S. Ferrari, C. Copelli, B. Bianchi, A. Ferri, E. Sesenna — 2011-12-08

Summary: The buccinator musculomucosal flaps are actually considered the main reconstructive option for small-moderate defects of the oral mucosa. In this paper we present our experience with the posteriorly based buccinator musculomucosal flap. A retrospective review was performed of all patients who had had a Bozola flap reconstruction at the Operative Unit of Maxillo-Facial Surgery of Parma, Italy, between 2003 and 2010. The Bozola flap was used in 19 patients. In most cases they had defects of the palate (n=12). All flaps were harvested successfully and no major complications occurred. Minor complications were observed in two cases. At the end of the follow up all patients returned to a normal diet without alterations of speech and swallowing. We consider the Bozola flap the first choice for the reconstruction of defects involving the palate, the cheek and the postero-lateral tongue and floor of the mouth.

Enforced expression of nuclear factor kappa B in p53 deficient keratinocytes induces cell cycle, angiogenic potential and tumorigenesis - Corrected Proof

Emiro E. Caicedo-Granados, Beverly R. Wuertz, Frank G. Ondrey — 2011-12-06

Summary: Multiple genetic mutations with subsequent molecular events are required for progression of normal epithelial cells to cancer, with p53 mutations being a very common event in squamous carcinogenesis. Upregulation of nuclear factor kappa B (NF-κB) is an associated feature of malignancy, however studies have not examined purposeful overexpression of the NF-κB p65 subunit in in vitro models of oral carcinogenesis. Our objective is to demonstrate that NF-κB p65 transfection into p53 deficient Rhek keratinocytes produces carcinogenic progression. We constitutively over-expressed NF-κB p65 in Rhek keratinocytes, previously immortalized by SV 40 thus inactivating p53, and studied NF-κB dependent events. NF-κB p65 overexpression provided functional upregulation of NF-κB and produced cyclin D1-mediated proliferation and interleukin 8 transcription and secretion. Consequently, we demonstrated tumorigenesis in athymic mice with NF-κB p65 overexpressing cells. We conclude NF-κB p65 overexpression in p53 inactivated immortalized keratinocytes produces tumorigenesis, and that this single alteration in NF-κB expression on a p53 inactivated background is sufficient for squamous carcinogenesis features, thus providing evidence that p65 may act as a gain of function oncogene in this setting.

Management of dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck receiving cetuximab and radiotherapy - Corrected Proof

Luis Cabezón Gutiérrez, Parham Khosravi-Shahi, Yolanda Escobar Álvarez — 2011-12-05

Summary: Locally advanced squamous cell carcinoma of the head and neck is generally managed with a combination of surgery, RT, and/or chemotherapy or cetuximab. Appropriate management of radiation dermatitis associated with cetuximab and radiotherapy is necessary to allow adequate drug administration and to improve the quality of life and outcome.We generate a recommendation for radiation dermatitis on the basis of a systematic revision of the literature.Radiation dermatitis is experienced by the majority of patients undergoing radiotherapy for HNSCC, generally being mild to moderate (grades 1–2), showing about 25% severe toxicity (grade⩾3). Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed.This paper reviews comprehensive consensus guidelines to help manage the radiation dermatitis in order to make an optimal use of available therapeutic arsenal.

Biomarker detection for the diagnosis of lymph node metastasis from oral squamous cell carcinoma - Corrected Proof

Ki-Yeol Kim, Gui Youn Lee, In-Ho Cha — 2011-12-05

Summary: Lymph node metastasis is an important prognostic factor in oral squamous cell carcinoma. However, the lack of significant biomarkers for lymph node metastasis can cause patients to be inappropriately treated and produce a poor prognosis. Therefore, there is a need to identify gene sets that are associated with lymph node metastasis. In this study, we used three expression datasets obtained from a public database and selected candidate gene sets that were related with lymph node metastasis from two datasets and a combined dataset. We evaluated the selected gene set using OOB error rates in a validation dataset. The gene set detected from the combined dataset classified the lymph node status more accurately in the validation dataset and clear expression patterns classifying the lymph node status based on chromosomal location were observed. The combined dataset holds promise for use as a more accurate candidate gene set for the diagnosis of lymph node metastasis and the selected gene set could be used for biological validation in further studies.

Functional and sensitive outcomes after tongue reconstruction: About a series of 30 patients - Corrected Proof

2011-12-02

Summary: Few studies reported both functional and sensitive long-term evaluations after tongue reconstruction. The aim of this study was to assess functional outcomes and sensitive recovery after tongue reconstruction with fasciocutaneous free flap (FCFF) or musculocutaneous pedicled flap (MCPF) without nerve anastomosis. We enrolled 30 patients having no recurrence from a consecutive series of 79 tongue reconstructions as part of a cancer treatment. All patients were submitted to functional and sensitive tests. The functional study included intelligibility, tongue motility, food, and swallowing scores. Flap sensibility was evaluated too. Male-to-female sex ratio was 6.5 with a mean age of 52years old. The lesions were mainly advanced (T3–T4 73%). Mobile tongue and base of tongue resection was carried out in 43% of cases, and resection was limited to the oral tongue for 53%. Twenty-one FCFF and nine MCPF were performed. The mean follow-up was 2years and 11months. Swallowing (slightly impaired 63%), food (normal 40%), and intelligibility (excellent 77%) assessments were satisfactory. Spontaneous sensory recovery was regularly observed (mean response 62%). The two groups FCFF and MCPF were similar regarding population and tumors characteristics. Functional results were higher in case of FCFF (food score p=0.05; intelligibility p=0.04). No difference was observed on sensitive recovery. This study emphasizes good functional results either for swallowing or intelligibility, with higher scores for the FCFF, strengthening the opinion that FCFF is the best choice for tongue reconstruction whenever possible.

Assessment and management of dysphagia in patients with head and neck cancer who receive radiotherapy in the United Kingdom – A web-based survey - Corrected Proof

2011-11-30

Summary: We undertook a service evaluation to establish how oropharyngeal dysphagia is managed in head and neck cancer patients receiving radiotherapy in the United Kingdom. A web-based survey including 23 open and closed questions was distributed to Speech and Language Therapy (SLT) teams via a national network of Royal College of Speech and Language Therapists (RCSLT) special interest groups with members involved in head and neck cancer care. Forty-six teams responded to the survey and 89% completed the questionnaire fully. Fifty percent (n=21/42) of the SLT teams reported routinely seeing patients prior to commencing radiotherapy. Baseline oromotor assessment (85.7% (n=36/42)), clinical dysphagia assessment (90.5% (n=38/42)) and information provision on the potential treatment effects on swallowing (97.6% (n=41/42)) and communication ability (85.7% (n=36/42)) were the most common components of initial evaluation. In keeping with expert opinion and emerging evidence, prophylactic swallowing exercises were administered by 71.4% (n=30/42) of teams targeting specific aspects of swallowing, although the nature, intensity and duration of programmes varied. A range of measures are used to monitor progress during treatment. Our survey highlighted that resource limitations affect service provision with some teams managing the consequences of treatment rather than proactive multidisciplinary intervention prior to and during treatment. Cancer- and treatment-related dysphagia can impact significantly on a broad range of outcomes following radiotherapy. There is variability in dysphagia service provision to patients before, during and following treatment. Comprehensive evaluation of swallowing function prior to treatment and proactive management can yield benefits for patients, inform multidisciplinary case management and support those involved in clinical trials to accurately determine treatment effects.

The Saxon Bisphosphonate Register – Therapy and prevention of bisphosphonate-related osteonecrosis of the jaws - Corrected Proof

2011-11-30

Summary: In 2009, a study group of three Saxon hospitals set up a Saxon register with the aim of including all patients with bisphosphonate (BP) medication. In addition, specific concepts for surgical approach were developed. The target is to define relevant treatment and prevention strategies of bisphosphonate-related osteonecrosis of the jaws (BRONJ) based on high patient population statistics. Since July 2009, all patients with oral or intravenous BP medication have been registered in the 3 Saxon hospitals. Data was systematically acquired in detailed forms. Totally, 258 patients (♂: 83, ♀: 175) were registered by October 2010. 100 patients out of this already had BRONJ which preferably affected the mandible (70%) and was mostly associated with intravenous medication. In 54 cases, treatment was carried out by surgery according to the strategy developed. The criterion for success was absence of symptoms at least for 3months after surgery. The following stage-dependent success rates were obtained: stage I (13 patients) – 84.6%, stage II (22 patients) – 95.5%, stage III (14 patients) – 85.7%, stage IV (5 patients) – 80%. Under preventive aspects, teeth were extracted after a predefined scheme in 68 of all patients registered as being asymptomatic. No BRONJ was observed in 98.5%; the criterion also being absence of symptoms for a minimum period of 3months after surgery. Surgical treatment is the treatment of choice in cases of BRONJ. Tooth extractions are rather unproblematic in asymptomatic patients if the predefined scheme is followed.

Tumour infiltration depth ⩾4mm is an indication for an elective neck dissection in pT1cN0 oral squamous cell carcinoma - Corrected Proof

2011-11-30

Summary: Patients with pT1cN0 oral squamous cell carcinomas (OSCC) are generally not treated with a neck dissection (ND). However, in 25% of cN0 patients, nodal metastases become apparent during follow-up. Infiltration depth of the primary tumour has been consistently associated with the presence of nodal metastasis, but proposed cut-off depths for performing a ND vary considerably. The aim of this study was to explore the infiltration depth as predictor for the nodal status and to recommend a cut-off depth for performing a ND.From our database of 351 primary oral carcinomas, we selected all pT1–2 tumours (n=246). Infiltration depth was measured in 212 cases. Neck status was determined by histopathological examination of the dissection specimen, or by at least two years of follow-up.Mean infiltration depth was 5.49mm (95% CI: 4.86–6.12) in the N0 and 8.40mm (95% CI: 7.38–9.43) in the N+ group (p<0.001). cN status, lymphovascular invasion and infiltration depth were the only independent predictors for nodal status in multiple logistic regression. ROC-analysis on pT1cN0 tumours resulted in an optimal cut-off for the prediction of the nodal status at a depth of 4.59mm. This cut-off identified a subgroup of patients at increased risk for nodal metastasis (OR=8.3) and with significantly shorter survival.Tumour infiltration depth is an independent predictor for nodal status in pT1–2 OSCC. In pT1cN0 tumours, a cut-off at 4.59mm results in the best predictive value.We recommend an infiltration depth of ⩾4mm as an indication to perform a neck dissection in pT1cN0 OSCC.

Prognostic significance of radiologically determined neck node volume in head and neck cancer: A systematic review - Corrected Proof

W.L. Lodder, F.A. Pameijer, C.R.N. Rasch, M.W.M. van den Brekel, A.J.M. Balm — 2011-11-23

Summary: This systematic review addresses the prognostic significance of neck node volume in head and neck cancer. Primary tumor volume evolved as an independent significant factor for survival in head and neck cancer patients. Besides primary tumor volume, multiple prognostic features related to the regional lymph nodes were studied in literature. In literature, some authors showed the significance of total tumor volume/nodal volume for survival and loco-regional control. Articles reporting prognosis and survival in nodal tumor volumes were collected by systematically reviewing publications listed in the Pubmed and Embase databases. Publications were included when they at least reported on total tumor volume (TTV) or nodal volume and survival.In this systematic review we studied 21 articles. For measurement of nodal volume different formulas were used. Until now, there’s no clear statistical evidence for the use of either TTV or nodal volume versus primary tumor volume to predict the individual loco-regional control or survival after treatment.There is wide variety of tumor measuring systems in the literature. The cut-off value for local tumor response also shows large variation. Firstly consensus should be accomplished on standardization of volume measurements, preferably automatic, and secondly large study groups are needed with identical treatment modalities to further unravel the role of neck node volume as separate staging tool.

The role of neck dissection in the setting of chemoradiation therapy for head and neck squamous cell carcinoma with advanced neck disease - Corrected Proof

2011-11-21

Summary: Concurrent chemotherapy and radiotherapy (CRT) has become standard treatment for many patients with advanced head and neck squamous cell carcinoma (HNSCC). This has led to controversy concerning the role of neck dissection (ND) in this setting. The current debate is focused on N2–N3 disease and the ability of a clinical complete response to predict the absence of viable cells in the ND specimen. Proponents of a systematic planned ND argue that it improves regional control and possibly disease-specific survival. They assert that a clinical response does not predict the pathologic response, and that in the event of recurrence in the neck, a surgical salvage procedure is unlikely to succeed. Conversely, there are many arguments in favor of performing ND only for patients who have evidence of residual neck disease because of the very low probability of isolated neck recurrence following a complete response. Proponents argue that for complete responders, planned ND is associated with no survival benefit. As planned surgery will only benefit patients with residual disease in the neck alone, there is a high rate of unnecessary ND with its associated morbidity. Another question concerns the appropriate type of ND to be performed. Even if required after chemoradiation, selective ND is oncologically feasible with minimal morbidity. Lastly, robust data from a randomized trial demonstrating the superiority of one approach vs. the other are lacking. After conducting a review of recent literature on the subject, the authors conclude that planned ND is not necessary for patients with complete response because of the availability of improved diagnostic follow up modalities, and the increased sensitivity to CRT of HNSCC, particularly HPV associated tumors.

Neck dissection field and lymph node density predict prognosis in patients with oral cavity cancer and pathological node metastases treated with adjuvant therapy - Corrected Proof

2011-11-21

Summary: Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy.We examined 309 pN+ patients who underwent levels I–III ND and 148 pN+ patients treated with levels I–V ND. The 5-year control and survival rates served as the main outcome measures.The 5-year rates for patients treated with levels I–III and I–V NDs were as follows: local control, 79%, 74% (p=0.0630); neck control, 81%, 68% (p=0.0014); distant metastasis, 21%, 36% (p=0.0003); disease-free survival (DFS), 59%, 43% (p=0.0001); disease-specific survival (DSS), 66%, 46% (p<0.0001); and overall survival (OS), 49%, 37% (p=0.0048), respectively. Multivariate analysis demonstrated that an LN density ⩾0.16 was an independent prognostic factor for 5-year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412–5.128]), distant metastases (0.001, 2.831 [1.520–5.270]), DFS (<0.001, 2.464 [1.571–3.866]), and DSS (0.036, 1.781 [1.040–3.052]) in levels I–III ND patients. An LN density ⩾0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654–14.344]), neck control (0.002, 24.738 [3.367–181.771]), DFS (<0.001, 4.151 [2.264–7.610]), DSS (<0.001, 3.791 [2.017–7.125]), and OS (<0.001, 2.806 [1.706–4.613]) in levels I–V ND patients.Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy.

Clinical significance of molecular alterations in histologically negative surgical margins of head and neck cancer patients - Corrected Proof

2011-11-21

Summary: The development of locoregional recurrence is the main reason for treatment failure in head and neck squamous cell carcinomas (HNSCC) and the remaining of tumor cells in surgical margins is associated with recurrence. Surgical margins are considered negative based on histologic assessment of the pathological specimen. However, this method lacks sensitivity in identifying cells that already started malignant transformation but have not yet developed a pathologic phenotype. We investigated the usefulness of assessing the expression of PTHLH, EPCAM, MMP9, LGALS1 and MET for the detection of molecular alterations in histologically negative surgical margins and determine the correlation of these tumor-related alterations with clinical and prognostic parameters. Differential gene expression was determined by quantitative RT–PCR analyses in normal mucosa, HNSCC and negative margin samples. Thirty-eight percent of the histologically negative surgical margins examined were margin-positive for overexpression of at least one of the genes evaluated. Moreover, MMP9 and PTHLH overexpression in the surgical margins was associated with the development of second primary tumors (p=0.002) and lower rates of local control (log rank test p=0.022; HR=4.186; p=0.035), respectively. These findings demonstrate that the overexpression of tumor-related genes in histologically negative surgical margins is a frequent event. The use of qRT–PCR may be an useful tool in detecting actually negative HNSCC surgical margins and the overexpression of specific genes in these margins could be helpful in the identification of patients with a higher risk of developing second primary tumors and local recurrences, thus aiding the surgeon in the delineation of the HNSCC resection extent and helping in the planning of adjuvant therapy.

Sinonasal inverted papilloma associated with malignancy: The role of human papillomavirus infection and its implications for radiotherapy - Corrected Proof

2011-11-18

Summary: Sinonasal inverted papilloma (IP) is a benign but destructive tumor originating from the ciliated respiratory mucosa of the sinonasal tract. It can be associated with malignancy (squamous cell histology, in particular) and human papillomavirus infection has been investigated as a potential etiological factor linked to malignant alterations of IP. Surgery is the treatment of choice for IP, however, radiotherapy as an adjunct to surgery is indicated for IP with associated malignancy.

Trends and inequalities in laryngeal cancer survival in men and women: England and Wales 1991–2006 - Corrected Proof

Libby Ellis, Bernard Rachet, Martin Birchall, Michel P. Coleman — 2011-11-17

Summary: Laryngeal cancer in men is a relatively common malignancy, with a marked socioeconomic gradient in survival between affluent and deprived patients. Cancer of the larynx in women is rare. Survival tends to lower than for men, and little is known about the association between deprivation and survival in women with laryngeal cancer. This paper explores the trends and socio-economic inequalities in laryngeal cancer survival in women, with comparison to men. We examined relative survival among men and women diagnosed with laryngeal cancer in England and Wales during 1991–2006, followed up to 31 December 2007. We estimated the difference in survival between the most deprived and most affluent groups (the ‘deprivation gap’) at one and five years after diagnosis, for each sex, anatomical subsite and calendar period. Five year survival for all laryngeal cancers combined was up to 8% lower in women than in men. This difference is only partially explained by the differential distribution of anatomical subsites in men and women. Disparities in survival between men and women were also present within specific subsites. In contrast to men, there was little evidence of a consistent deprivation gap in survival for women at any of the anatomical subsites. The stark socioeconomic inequalities in laryngeal cancer survival in men do not appear to be replicated in women. The origins of the socio-economic inequalities in survival among men, and the disparities in survival between men and women at specific tumour subsites remains unclear.

Adenoid cystic carcinoma of parotid gland treated with surgery and radiotherapy: Long-term outcomes, QoL assessment and review of the literature - Corrected Proof

2011-11-17

Summary: To assess outcomes, toxicity and quality-of-life (QoL) of patients with parotid gland adenoid cystic carcinoma (PGACC) treated by surgery and postoperative radiotherapy. Between 1995 and 2010, 46 patients with PGACC were treated with parotidectomy±neck dissection followed by radiotherapy. Endpoints were loco-regional control (LRC), distant metastasis-free (DMFS), disease-free (DFS), cause-specific (CSS), and overall survival (OS), late toxicity, and QoL. After a median follow-up of 58months (range 4–171), the 5-year Kaplan–Meier estimates of LRC, DMFS, DFS, CSS, and OS were 88%, 78%, 75%, 80%, and 67%, respectively and the 8-year rates were 88%, 75%, 72%, 77%, and 64%, respectively. On multivariate analysis, T-stage, N-stage, tumor grade, and perineural invasion correlate significantly with DMFS and DFS. The overall 5-year cumulative incidence of grade ⩾2 late toxicity was 9%. QoL-scores deteriorate during and shortly after treatment but returned in all scales to almost baseline levels within 6months. Excellent LRC rates were achieved in patients with PGACC treated by surgery and postoperative radiotherapy with low rate of late side-effects and preservation of good QoL. Despite the effective local therapy, 9 of 46 patients (20%) failed distantly. Because effective treatment strategies for this problem are lacking, prospective trials are needed to determine the role of adjuvant systemic or targeted therapy in patients at high risk of DM.

Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer - Corrected Proof

2011-11-14

Summary: In loco-regionally advanced head and neck squamous cell cancer (HNSCC), concurrent 3-weekly cisplatin improves overall survival (OS) compared to radiotherapy alone, but is often associated with renal toxicity. The use of radiotherapy with accelerated fractionation schedules has been reported to improve survival but its optimal combination with chemotherapy is unclear. Retrospective analysis of treatment outcome and nephrotoxicity of radiotherapy given with an intensity-modulated approach (IMRT) concurrent with either 3-weekly or weekly cisplatin in 94 patients with stage III/IV HNSCC. Patients treated with weekly cisplatin were significantly older (p=0.0014) and received a significantly lower total cisplatin dose (p=0.0002). With a median follow-up of 2.8years, at univariate analysis, 3-weekly cisplatin shows a longer OS (p=0.041) but progression-free survival (PFS) is similar for both schedules (p=0.47). Cisplatin doses >240mg/m2 were associated with better OS but not PFS. Chronic renal failure rate was significantly higher with 3-weekly cisplatin (p=0.04). Multivariate analysis (Cox regression controlling for age) confirmed the significant and independent impact of alcohol and smoking habits on both PFS (HR, 2.2) and OS (HR, 2.3), while the treatment schedule affected only OS (HR, 2.2). Weekly cisplatin is less nephrotoxic. Both schedules can be combined to curative IMRT. PFS was not significantly different even if patients treated with the weekly schedule were significantly older and received reduced cisplatin doses. The study suggests that the different cisplatin dose doesn’t affect the PFS results if concomitant to IMRT. Controlled prospective studies are needed.

EB-virus associated primary CD30-positive lymphoproliferative disease of the maxillary gingival in an immunocompetent woman - Corrected Proof

Tadashi Terada — 2011-11-14

Non-Hodgkin’s lymphoma (NHL) of the oral cavity is rare, but the second most common malignancy next to squamous cell carcinoma. NHL only account for 3.5% of all oral malignancies. The palatine tonsil is the most frequently involved site, followed by palate, gingival and tongue. The most common type of NHL of the oral cavity is diffuse large B-cell lymphoma (64%). followed by mantle cell lymphoma (10%), follicular lymphoma (8%), extranodal marginal zone B-cell lymphoma of MALT type (6.5%), T-cell lymphomas (6.5%), and Burkitt lymphoma (5%). The etiology NHL of the oral cavity is unknown in most patients. A minority of patients have an underlying immunodeficiency state such as HIV infection. There is a strong association with Epstain–Barr virus (EBV) in the setting of immunodeficiency as well as extranodal NK/T cell lymphoma of nasal type. MALT lymphoma may be associated with Sjogren syndrome. CD30-positive lymphoproliferative disorders (CD30PLPD) are most common in the skin. Cutaneous CD30PLPD includes lymphomatoid papulosis and anaplastic large cell lymphoma. The etiology of CD30PLPD is unknown. The survival is good with 10year survival of 90%. CD30PLPD including anaplastic large cell lymphoma (ALCL) of the oral cavity is extremely rare: only 13 cases have been reported. Most patients of CD30PLPD of the oral cavity are not associated with EBV. ALCL is also not associated with EBV. Only two patients with CD30PLPD associated with EBV have been reported in immunodeficiency patients due to human immunodeficiency virus (HIV). Herein reported is the first case of CD30PLPD of the maxillary gingival in an immunocompetent woman.

Involvement of viral factors with head and neck cancers - Corrected Proof

2011-11-11

Summary: The incidence of head and neck cancer remains high and is associated with many deaths in both Western and Asian countries. Common risk factors in head and neck carcinoma are smoking and alcohol abuse, however, in an increasing proportion of cases, no significant smoking or drinking history has been reported. The infectious nature of oncogenic viruses sets them apart from other carcinogenic agents. As such, a thorough study of both the pathogenesis of viral infection and the host response is crucial to a full understanding of the resulting cancers. Such an understanding, in turn, has increased our knowledge of cellular pathways involved in growth and differentiation and neoplasia as a whole. Even though human oncogenic viruses belong to different virus families and utilize diverse strategies to contribute to cancer development, they share many common features. Viruses linked to cancers in humans are the human papilloma viruses, Epstein-Barr virus, hepatitis C virus and human herpesvirus-8. The potential role and involvement of these viruses in head and neck cancers along with brief description of vaccine development is provided.

Toll-like receptor 3-mediated tumor invasion in head and neck cancer - Corrected Proof

Hui-Ching Chuang, Chao-Cheng Huang, Chih-Yen Chien, Jiin-Haur Chuang — 2011-11-09

Summary: Objectives: Chronic inflammation associated with some infectious agents can lead to cancer. The Toll-like receptor (TLR) family is one of the largest and best-studied families of pathogen-associated molecular patterns. TLR3 recognizes double-stranded RNA and is a major effector of the immune response against viral pathogens.Materials and methods: We investigated TLR3 protein expression in 153 oral squamous cell carcinoma (OSCC) specimens using tissue microarray. Furthermore, we used polyinosinic-polycytidylic acid (poly I:C) to stimulate head and neck cancer cells and an inhibitor of endosomal acidification bafilomycin A1 to block the TLR 3 signaling pathway to clarify the role of TLR 3 in OSCC.Results: Cytoplasmic TLR3 staining was observed in the vast majority of OSCC tissues (73.2%). Strong TLR3 expression was significantly correlated with patients whose tumors were poorly differentiated (P=0.028) and with perineural invasion (P=0.023). Three of the four head and neck cell lines tested (Fadu, OC2, and SCC4) expressed TLR3 mRNA, although at various levels. The stimulation of TLR3-expressing OC2 cells with poly I:C caused the phosphorylation of IFN regulatory factor 3 and IκB and sequentially induced the secretion of interleukin-6 and chemokine (C–C motif) ligand 5 (CCL5) in a dose- and time-dependent manner. Moreover, poly I:C stimulation promoted CCL5-mediated migration in OC2 cells.Conclusions: In this report, we provide a novel mechanism for tumor invasion and the TLR3-dependent inflammatory response that could have therapeutic implications for OSCC.

Proposed clinical classification for oral submucous fibrosis - Corrected Proof

2011-11-09

Summary: Oral Submucous Fibrosis (OSMF) is a chronic, progressive, scarring disease, that predominantly affects people of South Asia and South-East Asia, where chewing of arecanut and its commercial preparation is high. Presence of fibrous bands is the main characteristic feature of OSMF. Based on clinical and/or histopathological features of OSMF, various classifications have been put forth till date. But the advantages and drawbacks of these classification supersedes each other, leading to perplexity. Our various studies and clinical experience in the field of OSMF have initiated us to propose/introduce the new clinical classification which could assist the clinician in the categorization of this potentially malignant disorder according to its biological behaviour and hence its subsequent medical and surgical management.

VEGF-A immunohistochemical and mRNA expression in tissues and its serum levels in potentially malignant oral lesions and oral squamous cell carcinomas - Corrected Proof

2011-11-03

Summary: The aim of the study was to investigate whether the estimation of circulating Vascular endothelial growth factor-A (VEGF-A) levels by ELISA could be used as surrogate of VEGF-A expression in tissues of pre-malignant oral lesions (PMOLs) and oral squamous cell carcinoma (OSCC) as compared to that in healthy controls. The study samples comprised of tissue and blood samples from 60 PMOLs, 60 OSCC, and 20 healthy controls. Serum VEGF-A levels were determined by an ELISA based assay (Quantikine human VEGF; R & D System, Minneapolis USA). Tissue VEGF-A expression and microvessel density (MVD) were assessed by immunohistochemistry (IHC) using antibodies against VEGF-A and CD-34 on formalin fixed paraffin embedded (FFPE) tissue sections. VEGF-A mRNA expression was analyzed by real-time PCR in snap frozen tissues. Serum VEGF-A levels and immunohistochemical VEGF-A expression were significantly high in PMOLs and OSCC in comparison with controls. VEGF mRNA gene expression showed more than 50-fold increase in PMOLs and OSCC. VEGF-A levels in serum correlated in a linear fashion with the tissue expression in oral pre-malignant and malignant lesions, suggesting that the serum levels may serve as surrogate material for tissue expression of VEGF-A.