Most Cited Oral Oncology Articles
The most cited articles published since 2011, extracted from Scopus.
Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysisM. A. O'Rorke | M. V. Ellison | L. J. Murray | M. Moran | J. James | L. A. Anderson
Volume 48, Issue 12, December 2012, Pages 1191-1201
Human Papillomavirus (HPV) related oropharyngeal squamous cell carcinomas (OPSCCs) are reported to have improved prognosis and survival in comparison to other head and neck squamous cell cancers (HNSCCs). This systematic review and meta-analysis examines survival differences in HPV-positive HNSCC and OPSCC subtypes including tonsillar carcinoma in studies not previously investigated. Four electronic databases were searched from their inception till April 2011. A random effects meta-analysis was used to pool study estimates evaluating disease-specific (death from HNSCC), overall (all-cause mortality), progression-free and disease-free (recurrence free) survival outcomes in HPV-positive vs. HPV-negative HNSCCs. All statistical tests were two-sided. Forty-two studies were included. Patients with HPV-positive HNSCC had a 54% better overall survival compared to HPV-negative patients HR 0.46 (95% CI 0.37-0.57); the pooled HR for tonsillar cancer and OPSCC was 0.50 (95% CI 0.33-0.77) and HR 0.47 (95% CI 0.35-0.62) respectively. The pooled HR for disease specific survival was 0.28 (95% CI 0.19-0.40); similar effect sizes were found irrespective of the adjustment for confounders, HPV detection methods or study location. Both progression-free survival and disease-free survival were significantly improved in HPV-positive HNSCCs. HPV-positive HNSCCs and OPSCCs patients have a significantly lower disease specific mortality and are less likely to experience progression or recurrence of their cancer than HPV-negative patients; findings which have connotations for treatment selection in these patients. © 2012 Elsevier Ltd. All rights reserved.
Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomasMark W. Lingen | Weihong Xiao | Alessandra Schmitt | Bo Jiang | Robert Pickard | Paul Kreinbrink | Bayardo Perez-Ordonez | Richard C. Jordan | Maura L. Gillison
Volume 49, Issue 1, January 2013, Pages 1-8
Background: Human papillomavirus (HPV) is a cause of oropharyngeal cancer, but a role for HPV in the etiology of oral cavity squamous cell carcinomas (OCSCC) remains uncertain. Methods: We sought to estimate the etiologic fraction for HPV among consecutive, incident OCSCC diagnosed from 2005 to 2011 at four North American hospitals. DNA and RNA purified from paraffin-embedded tumors were considered evaluable if positive for DNA and mRNA control genes by quantitative PCR. Fifteen high-risk (HR) HPV types were detected in tumors by consensus PCR followed by type-specific HR-HPV E6/7 oncogene expression by quantitative reverse-transcriptase PCR. P16 expression was evaluated by immunohistochemistry (IHC). A study of 400 cases allowed for precision to estimate an etiologic fraction of as low as 0% (97.5% confidence interval, 0-0.92%). Results: Of 409 evaluable OCSCC, 24 (5.9%, 95%CI 3.6-8.2) were HR-HPV E6/7 expression positive; 3.7% (95%CI 1.8-5.5) for HPV16 and 2.2% (95%CI 0.8-3.6) for other HR-HPV types. HPV-positive tumors arose from throughout the oral cavity (floor of mouth [n = 9], anterior tongue , alveolar process , hard palate , gingiva  and lip ) and were significantly associated with male gender, small tumor stage, poor tumor differentiation, and basaloid histopathology. P16 IHC had very good-to-excellent sensitivity (79.2%, 95%CI 57.9-92.9), specificity (93.0%, 95%CI 90.0-95.3), and negative-predictive value (98.6%, 95%CI 96.8-99.6), but poor positive-predictive value (41.3%, 95%CI 27.0-56.8) for HR-HPV E6/7 expression in OCSCC. Conclusion: The etiologic fraction for HR-HPV in OCSCC was 5.9%. p16 IHC had poor positive predictive value for detection of HPV in these cancers. © 2012 Elsevier Ltd. All rights reserved.
MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablationCheng Chia Yu | Yi Wei Chen | Guang Yuh Chiou | Lo Lin Tsai | Pin I. Huang | Charn Yung Chang | Ling Ming Tseng | Shih Hwa Chiou | Sang Hue Yen | Ming Yung Chou | Pen Yuan Chu | Wen Liang Lo
Volume 47, Issue 3, March 2011, Pages 202-210
Head and neck cancer (HNC) is a prevalent cancer worldwide. Let-7 has been shown to function as a tumour suppressor by regulating multiple oncogenic signalling pathways. However, the role of let-7 in head and neck cancer (HNC) and in HNC-associated tumour initiating cells (TIC) remains unclear. In this study, we first demonstrated that let-7a expression was significantly decreased but that Nanog/Oct4 expression was increased in HNC tissues as compared to adjacent normal cells. Expression of let-7a in recurrent HNC tissue and in regional metastatic lymph nodes of HNC patients was also significantly decreased, but Nanog/Oct4 expression was increased as compared to the expression levels in the parental tumours. Consistently, the stemness genes were significantly up-regulated and let-7a was down-regulated in HNC-ALDH1 + cells relative to HNC-ALDH1- cells. Furthermore, lentiviral-mediated let-7a overexpression could significantly inhibit the stemness signature and the chemoresistant abilities of HNC-ALDH1+ cells. Most importantly, overexpression of let-7 or knockdown of Nanog in ALDH1+ cells effectively blocked tumour metastasis and significantly prolonged survival time in ALDH1+-transplanted immunocompromised mice. Overall, restoration of let-7a in HNC and HNC-TIC may be a new approach for the therapeutic treatment of HNC in the future. These results show that let-7a negatively modulates the expression of stemness genes and plays a role as a tumour suppressor in HNC by eliminating the putative HNC-TIC population. © 2010 Elsevier Ltd. All rights reserved.
Advances and applications of oral cancer basic researchSabrina Daniela Da Silva | Alfio Ferlito | Robert P. Takes | Ruud H. Brakenhoff | Mev Dominguez Valentin | Julia A. Woolgar | Carol R. Bradford | Juan P. Rodrigo | Alessandra Rinaldo | Michael P. Hier | Luiz P. Kowalski
Volume 47, Issue 9, September 2011, Pages 783-791
Cancer of the oral cavity accounts for almost 3% of cancer cases in the world. The incidence varies widely reflecting geographic differences in exposure to risk factors. The recent rise in younger age groups and females seen in many countries is of particular concern. Treatment and management of complications, locoregional recurrence and further primary tumors result in high morbidity and mortality especially when the disease is advanced stage at initial diagnosis. Progress in cancer research has provided abundant new knowledge about cellular processes and molecular biology underlying oral carcinogenesis and tumor progression. The present review attempts to summarize the current most widely-used research approaches and their application in the prevention, diagnosis, effective treatment, and improved outcome of oral cancer. © 2010 Elsevier Ltd. All rights reserved.
Down-regulation of the microRNA-99 family members in head and neck squamous cell carcinomaZujian Chen | Yi Jin | Dongsheng Yu | Anxun Wang | Ishrat Mahjabeen | Cheng Wang | Xiqiang Liu | Xiaofeng Zhou
Volume 48, Issue 8, August 2012, Pages 686-691
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. © 2012 Elsevier Ltd. All rights reserved.
The biology of head and neck cancer stem cellsZhaocheng Zhang | Manoel Sant Ana Filho | Jacques E. Nör
Volume 48, Issue 1, January 2012, Pages 1-9
Emerging evidence indicates that a small population of cancer cells is highly tumorigenic, endowed with self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells are considered the "drivers" of the tumorigenic process in some tumor types, and have been named cancer stem cells. Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to the acquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype that may contribute to tumor recurrence and metastasis. Cancer stem cells have been identified in human head and neck squamous cell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase (ALDH) activity. The head and neck cancer stem cells reside primarily in perivascular niches in the invasive front where endothelial-cell initiated events contribute to their survival and function. In this review, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells, with a focus on the impact of these cells to head and neck tumor progression. © 2011 Elsevier Ltd. All rights reserved.
Cancer stem cell traits in squamospheres derived from primary head and neck squamous cell carcinomasYoung Chang Lim | Se Yeong Oh | Yun Yi Cha | Sung Hak Kim | Xun Jin | Hyunggee Kim
Volume 47, Issue 2, February 2011, Pages 83-91
A subpopulation of cancer stem cells (CSCs), but not the majority of non-tumorigenic cancer cells, in a variety of human malignancies plays a critical role in cancer cell proliferation, invasion, metastasis, and tumor recurrence post-therapies. We report the isolation of sphere-forming cells (squamospheres) from primary head and neck squamous cell carcinomas (HNSCCs), and characterization of their CSC properties. Squamospheres appeared within 2 weeks after seeding as single-dissociated cells obtained from primary HNSCC specimens in serum-free culture conditions. Real-time RT-PCR and immunocytochemistry assays revealed that a number of stem cell markers, including CK5, OCT4, SOX2, and nestin, were up-regulated in HNSCC-driven squamospheres. Fluorescence-activated cell sorting (FACS) analysis showed that squamospheres contain enriched side population cells compared to serum-induced differentiated squamosphere cells. Furthermore, HNSCC-driven squamospheres appeared to be chemoresistant to cisplatin, 5-fluorouracil (FU), paclitaxel and doxetaxel, and showed increased levels of ABCG2, one of the ATP-binding cassette (ABC) transporters. Of particular interest, in sharp contrast to subcutaneous injection of 1 × 106 differentiated squamosphere cells, as few as 100 squamosphere cells were able to give rise to tumors in nude mice. Altogether, we assert that primary HNSCC-driven squamospheres possess CSC properties, and its functional analysis may provide a novel tool for investigating the tumorigenic process of HNSCC. © 2010 Elsevier Ltd. All rights reserved.
Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancerShao Hui Huang | Bayardo Perez-Ordonez | Ilan Weinreb | Andrew Hope | Christine Massey | John N. Waldron | John Kim | Andrew J. Bayley | Bernard Cummings | B. C. John Cho | Jolie Ringash | Laura A. Dawson | Lillian L. Siu | Eric Chen | Jonathan Irish | Patrick Gullane | Angela Hui | Fei Fei Liu | Xiaowei Shen | Wei Xu | Brian O'Sullivan
Volume 49, Issue 1, January 2013, Pages 79-85
Objectives: To describe the natural course of distant metastases (DMs) following radiotherapy (RT) or chemoradiotherapy (CRT) in HPV(+) oropharyngeal carcinoma (OPC). Methods: OPC treated with RT/CRT from 1/1/2000 to 5/31/2010 were reviewed. The natural course of DM were compared between HPV(+) and HPV(-) cohorts. Results: Median follow-up was 3.9 years. The DM rate were similar (11% vs. 15% at 3-years, p = 0.25) between the HPV(+) (n = 457) vs. the HPV(-) (n = 167) cases. While almost all (24/25) HPV(-) DM occurred within 2-years following RT (1 was at 2.1 years), 7/54 (13%) of HPV(+) DM were detected beyond 3 years (up to 5.3 years). Disseminating to >2 organs occurred in 18 (33%) HPV(+) vs. none in HPV(-). Post-DM survival rates were 11% vs. 4% at 2-years (p = 0.02) for the HPV(+) vs. HPV(-) cases respectively. 5/6 HPV(+) with lung oligo-metastasis were still alive with stable disease beyond 2-years after salvage procedures for DM (chemotherapy: 3; surgical resection: 2; radiotherapy: 1). Conclusions: Although DM rates are similar, the natural course of HPV(+) DM differs from that of HPV(-) patients: it may occur after a longer interval, often with a "disseminating" phenotype, and a small number may have prolonged survival after salvage for DM. © 2012 Elsevier Ltd. All rights reserved.
Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancerDevasena Anantharaman | Manuela Marron | Pagona Lagiou | Evangelia Samoli | Wolfgang Ahrens | Hermann Pohlabeln | Alena Slamova | Miriam Schejbalova | Franco Merletti | Lorenzo Richiardi | Kristina Kjaerheim | Xavier Castellsague | Antonio Agudo | Renato Talamini | Luigi Barzan | Tatiana V. MacFarlane | Martin Tickle | Lorenzo Simonato | Cristina Canova | David I. Conway | Patricia A. McKinney | Peter Thomson | Ariana Znaor | Claire M. Healy | Bernard E. McCartan | Mia Hashibe | Paul Brennan | Gary J. MacFarlane
Volume 47, Issue 8, August 2011, Pages 725-731
Tobacco and alcohol are major risk factors for upper aerodigestive tract (UADT) cancer and significant variation is observed in UADT cancer rates across Europe. We have estimated the proportion of UADT cancer burden explained by tobacco and alcohol and how this varies with the incidence rates across Europe, cancer sub-site, gender and age. This should help estimate the minimum residual burden of other risk factors to UADT cancer, including human papillomavirus. We analysed 1981 UADT cancer cases and 1993 controls from the ARCAGE multicentre study. We estimated the population attributable risk (PAR) of tobacco alone, alcohol alone and their joint effect. Tobacco and alcohol together explained 73% of UADT cancer burden of which nearly 29% was explained by smoking alone, less than 1% due to alcohol on its own and 44% by the joint effect of tobacco and alcohol. Tobacco and alcohol together explained a larger proportion of hypopharyngeal/laryngeal cancer (PAR = 85%) than oropharyngeal (PAR = 74%), esophageal (PAR = 67%) and oral cancer (PAR = 61%). Tobacco and alcohol together explain only about half of the total UADT cancer burden among women. Geographically, tobacco and alcohol explained a larger proportion of UADT cancer in central (PAR = 84%) than southern (PAR = 72%) and western Europe (PAR = 67%). While the majority of the UADT cancers in Europe are due to tobacco or the joint effect of tobacco and alcohol, our results support a significant role for other risk factors in particular, for oral and oropharyngeal cancers and also for UADT cancers in southern and western Europe. © 2011 Elsevier Ltd. All rights reserved.
Bisphosphonate-related osteonecrosis of the jaws - A reviewSebastian Kühl | Christian Walter | Stephan Acham | Roland Pfeffer | J. Thomas Lambrecht
Volume 48, Issue 10, October 2012, Pages 938-947
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. © 2012 Elsevier Ltd. All rights reserved.
Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinomaLinda Lotta Kokko | Saija Hurme | Sanna Mari Maula | Kalle Alanen | Reidar Grénman | Ilpo Kinnunen | Sami Ventelä
Volume 47, Issue 6, June 2011, Pages 510-516
In several recent studies, CD44 expression has been associated with aggressive behavior in cancers of different types. CD44 expression is also linked to cancer stem cells, which have been shown to play a significant role in tumor progression and poor prognosis in head and neck squamous cell carcinoma (HNSCC), as well as in other cancers. Although CD44 is a potential prognostic marker, it has not been adopted to wider clinical use as a part of treatment planning in HNSCC patients. The aim of this research was to study whether CD44 overexpression is associated with 5 year overall survival in HNSCC. We also studied site-specific associations between increased CD44 expression and 5 year overall survival. Associations between relative tumor CD44 expressions and smoking, heavy alcohol consumption, histological grade of cancer, TNM staging and HNSCC staging were also studied. In total, 135 paraffin-embedded blocks from HNSCC patients were stained immunohistochemically with a CD44 antibody and were classified by the anatomic location of the tumor. CD44 overexpression had statistically significant association with decreased 5 year survival rates when all HNSCC samples were studied (p < 0.001). Significant association between intense CD44 expression and poor 5 year survival rates was found in the patients with SCC of the oro- and hypopharynx (p < 0.001) and the larynx (p = 0.042). In patients suffering from HNSCC in the oral cavity, CD44 overexpression did not have a significant effect on overall 5 year survival rates. Heavy smoking of over 10 pack years had a significant association with tumor CD44 overexpression (p = 0.009). Only pharyngeal (p = 0.046) and laryngeal (p = 0.047) SCC, but not oral-cavity SCC, had statistically significant associations between heavy smoking and CD44 overexpression when HNSCC was studied in regional groups. Alcohol consumption and tumor grade did not have a significant association with the tumor's CD44 expression. Our results suggest that CD44 overexpression could be used as a sign of aggressiveness, in addition to the HNSCC staging, as a prognostic factor in pharyngeal and laryngeal HNSCC and to assist in treatment selection. © 2011 Elsevier Ltd. All rights reserved.
Epithelial to mesenchymal transition (EMT) biomarkers - E-cadherin, beta-catenin, APC and Vimentin - In oral squamous cell carcinogenesis and transformationS. Y. Chaw | A. Abdul Majeed | A. J. Dalley | A. Chan | S. Stein | C. S. Farah
Volume 48, Issue 10, October 2012, Pages 997-1006
Objectives: To investigate immunohistochemical (IHC) analysis of E-cadherin, β-catenin, APC and Vimentin for prediction of oral malignant transformation. Materials and methods: Immunoreactivity for E-cadherin, β-catenin, APC and Vimentin were determined for 100 oral biopsies classified as normal, mild dysplasia, moderate-severe dysplasia or OSCC, using the IHC scoring or label index scoring systems. Co-expression of biomarkers and correlation with histopathological grading was analysed. Vimentin and E-cadherin results were confirmed by RT-PCR and further investigated in vitro using a novel organotypic cell invasion model based on human dermis. Results: A trend for decreased E-cadherin expression but increased Vimentin expression that correlated with increased disease severity was observed. Epithelial β-catenin localisation shifted from being membranous to cytoplasmic/nuclear with increased histopathological grade severity. Relative to normal, APC expression was decreased for mild dysplasia but increased for OSCC. Co-expression of β-catenin, APC and Vimentin (Spearman rank correlation) suggests interdependence of these molecules and involvement of the Wnt pathway in oral malignant transformation. Relative mRNA expression of E-cadherin for dysplasia and OSCC were less than 1% of normal tissue values, and mRNA expression of Vimentin was 3.7 times higher for OSCC than normal. After 63 days of organotypic culture neoplastic oral keratinocytes (PE/CA-PJ15) lost expression of E-cadherin and gained expression of Vimentin relative to their non-invasive counterparts in the epithelium. Conclusions: Trends in the expression of EMT markers - E-cadherin, β-catenin, APC and Vimentin - suggest their involvement in oral carcinogenesis via Wnt pathway dysregulation. Aberrant expression of β-catenin, APC and Vimentin are potential markers of malignant transformation. © 2012 Elsevier Ltd. All rights reserved.
A meta-analysis of the randomized controlled trials on elective neck dissection versus therapeutic neck dissection in oral cavity cancers with clinically node-negative neckAyotunde J. Fasunla | Brandon H. Greene | Nina Timmesfeld | Susanne Wiegand | Jochen A. Werner | Andreas M. Sesterhenn
Volume 47, Issue 5, May 2011, Pages 320-324
There is still no consensus on the optimal treatment of the neck in oral cavity cancer patients with clinical N0 neck. The aim of this study was to assess a possible benefit of elective neck dissection in oral cancers with clinical N0 neck. A comprehensive search and systematic review of electronic databases was carried out for randomized trials comparing elective neck dissection to therapeutic neck dissection (observation) in oral cancer patients with clinical N0 neck. A meta-analysis of the studies which met our defined selection criteria was performed using disease-specific death as the primary outcome, and the relative risk (RR) of disease-specific death was calculated for each of the identified studies. Both fixed-effects (Mantel-Haenszel method) and random-effects models were applied to obtain a combined RR estimate, although between-study heterogeneity was not found to be significant as indicated by an I2 of 8.5% (p = 0.350). Four studies with a total of 283 patients met our inclusion criteria. The results of the meta-analysis showed that elective neck dissection reduced the risk of disease-specific death (fixed-effects model RR = 0.57, 95% CI 0.36-0.89, p = 0.014; random-effects model RR = 0.59, 95% CI 0.37-0.96, p = 0.034) compared to observation. This reduction in disease-specific death rate supports the need to perform elective neck dissection in oral cancers with clinical N0 neck. © 2011 Elsevier Ltd. All rights reserved.
Clinical significance of genetic alterations and expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomasBalázs Szabó | Györgyi A. Nelhubel | Adél Kárpáti | István Kenessey | Balázs Jóri | Csilla Székely | István Peták | Gábor Lotz | Zita Hegedus | Balázs Hegedus | Tibor Füle | Balázs Döme | József Tímár | József Tóvári
Volume 47, Issue 6, June 2011, Pages 487-496
The significance of epidermal growth factor receptor (EGFR) signaling is well studied in a number of different tumors, but limited data is available with regard to head and neck squamous cell carcinoma (HNSCC). Since anti-EGFR therapies are currently under investigation in these malignancies as well, comprehensive information about the alteration of EGFR in HNSCC is necessary to design the most appropriate therapeutic protocols. We examined retrospectively the gene copy number of EGFR by FISH and the protein expression by immunohistochemistry using different epitope-specific antibodies in paraffin-embedded primary tumors of five different regions, from 71 HNSCC patients who had not been treated with anti-EGFR therapy. In seven cases corresponding lymph node metastases were also available for comparative analyses. We also determined the mutational status of tyrosine kinase (TK) domain (exon 19 and 21) and the extracellular deletion mutation (vIII) of EGFR, the KRAS mutation at codon 12 and the presence of HPV infection. Eight of the 71 cases (11.3%) showed EGFR gene amplification (most of them localized into the hypopharyngeal region) and the increased gene copy number (amplification + polysomy) was 43.7%. Despite pronounced intratumoral heterogeneity of EGFR protein expression being found, the high EGFR expression correlated with poor prognosis. On the other hand, the phosphorylation of EGFR was associated with prolonged survival. No mutations in the TK domain of EGFR were found in any of the HNSCC patients and only two cases were KRAS mutant at codon 12. We detected vIII deletion mutation of EGFR in 21% of the samples, but there was no statistically significant correlation between the presence of vIII mutant form and patient survival. EGFR vIII mutation was, however, associated with increased gene copy number. Fourteen of 71 cases (19.7%) were HPV-positive and the incidence of infection showed a decreasing tendency from the oral cavity towards the larynx. Interestingly, in contrast to previous findings, we could not observe improved survival in HPV-positive patients compared to non-infected patients, most probably due to the fact that the majority of these HNSCC patients were smokers and alcohol consumers. In conclusion, we found that increased EGFR protein levels and gene copy numbers (not gene amplification alone) have prognostic significance in the investigated HNSCC patient population. However, the relatively high incidence of the EGFR-vIII mutant form warrants careful therapeutic decision-making when choosing between different anti-EGFR treatment options. © 2011 Elsevier Ltd. All rights reserved.
Evaluation of an autofluorescence based imaging system (VELscope™) in the detection of oral potentially malignant disorders and benign keratosesK. H. Awan | P. R. Morgan | S. Warnakulasuriya
Volume 47, Issue 4, April 2011, Pages 274-277
Early detection of oral cancer is crucial in improving survival rate. Identification and detection of oral potentially malignant disorders (OPMD) allow delivery of interventions to reduce the evolution of these disorders to malignancy. A variety of new and emerging diagnostic aids and adjunctive techniques are currently available to potentially assist in the detection of OPMD. The objective of the present study was to evaluate the accuracy of autofluorescence against conventional oral examination and surgical biopsy. A total of 126 patients, 70 males and 56 females (mean age 58.5 ± 11.9 years) who presented to the Oral Medicine Clinics at King's and Guy's Hospitals, London with oral white and red patches suspicious of OPMD were enrolled. Following a complete visual and autofluorescence examination, all underwent an incisional biopsy for histopathological assessment. Seventy patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, 9 chronic hyperplastic candidiasis and rest frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 105 (83%) showed loss of fluorescence. Following biopsy 44 had oral epithelial dysplasia (29 mild, 8 moderate and 7 severe). The sensitivity (se) and specificity (sp) of autofluorescence for the detection of a dysplastic lesion was 84.1% and 15.3% respectively. While VELscope was useful in confirming the presence of oral leukoplakia and erythroplakia and other oral mucosal disorders, the device was unable to discriminate high-risk from low-risk lesions. © 2011 Elsevier Ltd. All rights reserved.
Saliva: A potential media for disease diagnostics and monitoringJingyi Liu | Yixiang Duan
Volume 48, Issue 7, July 2012, Pages 569-577
Within the past 10 years, the use of saliva as a diagnostic tool has gained considerable attention and become a well-accepted method. As a diagnostic fluid, saliva offers superiority over serum due to both a noninvasive collection method by specially trained persons and a cost-effective approach for screening of large populations. Collection of saliva offers a reduced risk of infection compared to the collection of serum. Moreover, obtaining saliva samples from infant, disabled or anxious patients, is much easier than obtaining other samples. There is a lot of useful components-changing information in saliva when a person is in sick. Therefore, we define these changing components as "biomarkers". The utilization of biomarkers as early predictors for clinical disease not only contributes to the effective prevention and treatment of diseases, but also enhances the assessment of potential health risks. In this article, we have reviewed the properties of saliva, the salivary analysis method for biomarker discovery, and the diagnostic potentials of salivary biomarkers in monitoring and detecting periodontal disease, Oral and Breast cancers, and Sjögren's syndrome. We also discussed some barriers of applications of saliva as a diagnostic media as well as recent improvements. We also prospected the future processing directions of using biomarkers in disease diagnosis and draw a conclusion that saliva is indeed an effective media in various disease monitoring and diagnosis. © 2012 Elsevier Ltd. All rights reserved.
Epithelial to mesenchymal transition in head and neck squamous cell carcinomaAshley Smith | Theodoros N. Teknos | Quintin Pan
Volume 49, Issue 4, April 2013, Pages 287-292
Epithelial to mesenchymal transition (EMT) is a dynamic cellular process that is essential for the development of metastatic disease. During EMT, a tumor cell with epithelial characteristics transitions to a tumor cell with mesenchymal characteristics through modulation of cell polarity and adhesion. Two hallmark EMT proteins, E-Cadherin and Vimentin, are tightly controlled during EMT through multiple signal transduction pathways. Epidermal growth factor (EGF) and transforming growth factorβ (TGFβ) promote EMT by regulating a distinct set of transcription factors, including Snail and Twist. Snail, Twist, and Slug are integral to the induction of EMT through direct regulation of genes involved in cellular adhesion, migration, and invasion. This review highlights the current literature on EMT in HNSCC. Understanding the role of EMT will provide insight to the pathogenesis of disease progression and may lead to the development of novel anti-cancer therapeutics for metastatic HNSCC. © 2012 Elsevier Ltd. All rights reserved.
Oral complications of targeted cancer therapies: A narrative literature reviewA. L. Watters | J. B. Epstein | M. Agulnik
Volume 47, Issue 6, June 2011, Pages 441-448
The aim of the present study was to investigate the available literature regarding the oral side effects or adverse events associated with targeted cancer therapy. Common oral toxicities include the terms mucositis, stomatitis, dysphagia, xerostomia, pharyngitis, and taste alterations. Aims of treatment included molecules and pathways involved in carcinogenesis reported in the literature were EGFRI, VEGF, mTOR, mAbs, TKIs, and multi-kinase inhibitors. Common targeted therapies used in clinical practice or under-investigation included cetuximab, panitumumab, erlotinib, sorafenib, sunitinib malate, imatinib mesylate, bevacizumab, trastuzumab, lapatinib, and mTORs. One hundred and forty-three articles were considered relevant and included in this review. The majority of studies did not specifically address oral toxicities or include an oral clinical exam, which may lead to underreported and under-investigated oral toxicities. Further investigation is necessary to determine if the initial impression that targeted therapy produces milder oral toxicities than conventional cancer treatment is accurate. © 2011 Elsevier Ltd. All rights reserved.
Isolation and characterization of cancer stem-like side population cells in human oral cancer cellsSouichi Yanamoto | Goro Kawasaki | Shin Ichi Yamada | Izumi Yoshitomi | Toshihiro Kawano | Hisanobu Yonezawa | Satoshi Rokutanda | Tomofumi Naruse | Masahiro Umeda
Volume 47, Issue 9, September 2011, Pages 855-860
Recent studies suggest that cancer stem cells may be responsible for tumorigenesis and contribute to some individuals' resistance to cancer therapy. Some studies demonstrate that side population (SP) cells isolated from diverse cancer cell lines harbor stem cell-like properties; however, there are few reports examining the role of SP cells in human oral cancer. To determine whether human oral cancer cell lines contain a SP cell fraction, we first isolated SP cells by fluorescence activated cell sorting, followed by culturing in serum-free medium (SFM) using the SCC25 tongue cancer cell line, so that SP cells were able to be propagated to maintain the CSC property. Differential expression profile of stem cell markers (ABCG2, Oct-4 and EpCAM) was examined by RT-PCR in either SP cells or non-SP cells. Growth inhibition by 5-FU was determined by the MTT assay. Clonogenic ability was evaluated by colony formation assay. SCC25 cells contained 0.23% SP cells. The fraction of SP cells was available to grow in SFM cultures. SP cells showed higher mRNA expression of stem cell markers (ABCG2, Oct-4 and EpCAM) as compared with non-SP cells. Moreover, SP cells demonstrated more drug resistance to 5-FU, as compared with non-SP cells. The clone formation efficiency of SP cells was significantly higher than non-SP cells at an equal cell number (P < 0.01). We isolated cancer stem-like SP cells from an oral cancer cell line. SP cells possessed the characteristics of cancer stem cells, chemoresistance, and high proliferation ability. Further characterization of cancer stem-like SP cells may provide new insights for novel therapeutic targets. © 2010 Elsevier Ltd. All rights reserved.
Surgery-triggered and non surgery-triggered Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ): A retrospective analysis of 567 cases in an Italian multicenter studyPaolo Vescovi | Giuseppina Campisi | Vittorio Fusco | Giovanni Mergoni | Maddalena Manfredi | Elisabetta Merigo | Luigi Solazzo | Mario Gabriele | Giovanni M. Gaeta | Gianfranco Favia | Franco Peluso | Giuseppe Colella
Volume 47, Issue 3, March 2011, Pages 191-194
Invasive local procedures are often reported in clinical history of patients suffering from Bisphosphonates-Related Osteonecrosis of the Jaws (BRONJ) but over 40% of spontaneous forms have been also described in literature. We compared age, gender, underlying bone disorders, bisphosphonate therapy, clinical features and surgical outcome of 205 cases (36.2%) of BRONJ non surgery-triggered (group 1) with 362 (63.8%) cases of surgery-triggered forms (group 2). Differences between group 1 and 2 were analysed using Mann-Whitney U and χ2 tests. Statistical analysis was performed using STATA 8. Zoledronate was the most used type of bisphosphonate (63.4% versus 69.0%) and the mandible was the most frequently involved site (63.9% versus 63.4%) in both groups. BRONJ in group 1 was more frequently multicentric (9.3% versus 5%, p < 0.05), had a lower clinical stage (45.9% versus 13.8% in stage 1, p < 0.01) and had a better outcome after surgical therapy (improvement in 74.1% versus 58.6%, p < 0.05). The high prevalence of non surgery-triggered forms of BRONJ should be considered by oncologists, haematologists and general physicians who are advised to inform their patients regarding the importance of preventive dental protocols to control the possible causes of osteonecrosis not related to dental invasive procedures. © 2010 Elsevier Ltd. All rights reserved.
MicroRNAs: New actors in the oral cancer sceneBo Hai Wu | Xue Peng Xiong | Jun Jia | Wen Feng Zhang
Volume 47, Issue 5, May 2011, Pages 314-319
MicroRNAs (miRNAs) are a group of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that mediate gene expression at the post-transcriptional level through mRNA degradation or translational repression. They are involved in regulating diverse cellular biological processes such as cell cycle, differentiation and apoptosis. Deregulation of miRNAs affects normal biological processes leading to malignancies, including oral squamous cell carcinoma (OSCC). Recent studies have identified aberrant miRNA expression profiles in OSCC tissues and/or cell lines compared with matched normal controls, the mechanisms of which are becoming unveiled. In addition, a small number of dysregulated miRNAs have been implicated either as oncogenes or tumor suppressors, affecting the initiation and progression of OSCC through the regulation of proliferation, apoptosis, metastasis and chemoresistance. Also, these missexpressed miRNAs have been shown to have potential as novel diagnostic, prognostic and therapeutic tools, which are expected to advance the clinical management of OSCC in the near future. © 2011 Elsevier Ltd. All rights reserved.
Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: A meta-analysis, 1985-2010Vijayvel Jayaprakash | Mary Reid | Elizabeth Hatton | Mihai Merzianu | Nestor Rigual | James Marshall | Steve Gill | Jennifer Frustino | Gregory Wilding | Thom Loree | Saurin Popat | Maureen Sullivan
Volume 47, Issue 11, November 2011, Pages 1048-1054
Human papillomavirus (HPV) types 16 and 18 are causally related to a sub-set of oral cavity and oropharyngeal squamous cell cancers. However, a clear estimate of the prevalence of HPV-16/18 in oral cavity and oropharyngeal dysplasia (OOPD) is not available. This literature review and meta-analysis was conducted to provide a prevalence estimate for HPV-16/18 in OOPD. Twenty-two studies that reported prevalence of HPV-16 and/or 18 in 458 OOPD lesions were analyzed. Meta-analysis was used to evaluate the prevalence of HPV-16/18 and logistic regression was used for stratified analysis by age, gender, and histological grade. The overall prevalence of HPV-16/18 in OOPD lesions was 24.5% [95% confidence interval (CI), 16.4-36.7%)]. The individual prevalence for HPV-16 alone was 24.4%. The prevalence of HPV-16/18 in oral cavity lesions alone was 25.3% (95% CI, 14.2-45.2%). The odds of detection of HPV-16/18 in dysplastic lesions in males were twice that of females [odds ratio (OR), 2.44]. HPV-16/18 were 3 times more common in dysplastic lesions (OR, 3.29; 95% CI, 1.95-5.53%) and invasive cancers (OR, 3.43; 95% CI, 2.07-5.69%), when compared to normal biopsies. There was no significant difference in HPV-16/18 rates between dysplastic lesions and cancers or between mild, moderate or severe dysplastic lesions. This meta-analysis provides a quantification of the prevalence of HPV types 16/18 in OOPD lesions. These results also support the assumption that HPV-16/18 infection occurs during the early phase of the oral cavity and oropharyngeal carcinogenesis. © 2011 Elsevier Ltd. All rights reserved.
Comparison between free flap and pectoralis major pedicled flap for reconstruction in oral cavity cancer patients - A quality of life analysisChih Yu Hsing | Yong Kie Wong | Ching Ping Wang | Chen Chi Wang | Rong San Jiang | Fun Jou Chen | Shih An Liu
Volume 47, Issue 6, June 2011, Pages 522-527
We aimed to compare the differences between free flap and pectoralis major myocutaneous flap (PMMF) for reconstruction in oral cavity cancer patients. Patients who received free flap or PMMF reconstruction after ablation surgeries were eligible for the current study. The patients' demographic data, medical history, and quality of life scores were collected and analyzed. A total of 491 patients' records were obtained. Among them, 100 patients completed a quality of life questionnaire. No significant differences could be found in age, morbidity, stage, and hospitalization between the free flap and PMMF groups. However, there were significant differences between both groups in gender, primary site, peri-operative blood loss, and operation duration. Patients reconstructed with free flap had better speech and shoulder functions as well as better mood status. Data from this study provide useful information for physicians and patients during their discussion of treatment modalities for oral cancers. © 2011 Elsevier Ltd. All rights reserved.
Near-infrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patientsJoost R. Van Der Vorst | Boudewijn E. Schaafsma | Floris P R Verbeek | Stijn Keereweer | Jeroen C. Jansen | Lilly Ann Van Der Velden | Antonius P M Langeveld | Merlijn Hutteman | Clemens W G M Löwik | Cornelis J H Van De Velde | John V. Frangioni | Alexander L. Vahrmeijer
Volume 49, Issue 1, January 2013, Pages 15-19
Objectives: Elective neck dissection is frequently performed during surgery in head and neck cancer patients. The sentinel lymph node (SLN) procedure can prevent the morbidity of a neck dissection and improve lymph node staging by fine pathology. Near-infrared (NIR) fluorescence imaging is a promising technique to identify the sentinel lymph node (SLN) intraoperatively. This feasibility study explored the use of indocyanine green adsorbed to human serum albumin (ICG:HSA) for SLN mapping in head and neck cancer patients. Materials and methods: A total of 10 consecutive patients with oral cavity or oropharyngeal cancer and a clinical N0 neck were included. After exposure of the neck, 1.6 mL of ICG:HSA (500 μM) was injected at four quadrants around the tumor. During the neck dissection, levels I-IV were measured for fluorescence using the Mini-FLARE imaging system. Results: In all 10 patients, NIR fluorescence imaging enabled visualization of one or more SLNs. A total of 17 SLNs were identified. The mean contrast between the fluorescent signal of the lymph nodes and of the surrounding tissue was 8.7 ± 6.4. In 3 patients, of which 1 was false-negative, lymph node metastases were found. After administration of ICG:HSA, the average number of fluorescent lymph nodes significantly increased over time (P < 0.001). Conclusion: This study demonstrated feasibility to detect draining lymph nodes in head and neck cancer patients using NIR fluorescence imaging. However, the fluorescent tracer quickly migrated beyond the SLN to higher tier nodes. © 2012 Elsevier Ltd. All rights reserved.
A review of oral toxicity associated with mTOR inhibitor therapy in cancer patientsFabiana Martins | Márcio Augusto De Oliveira | Qian Wang | Stephen Sonis | Marina Gallottini | Suzanne George | Nathaniel Treister
Volume 49, Issue 4, April 2013, Pages 293-298
Aphthous-like stomatitis has been identified as one of the most common dose-limiting toxicities associated with mTOR inhibitor therapy in cancer patients. The objective of this study was to summarize the cumulative oral toxicities associated with mTOR inhibitors in published oncology trials with respect to dose, schedule, and need for dose modifications. A review of all oncology-related clinical trials of mTOR inhibitors was conducted and standardized data was abstracted from each study. 44 studies were included in the analysis with a total of 2822 patients treated with temsirolimus (19 studies), everolimus (20 studies), and ridaforolimus (five studies) for a wide range of malignancies. At least one adverse event (AE) occurred in 74.4% of patients. Mucositis was the most frequent AE overall (73.4%), the third most frequent severe AE (20.7%), accounting for 27.3% dose reductions and 13.1% of discontinuations, and the most frequent dose limiting toxicity (52.5%). Mucositis typically occurred during the first cycle of therapy and was graded as mild to moderate in approximately 90% of the patients; severe mucositis generally occurred at higher doses. There were no clear differences in mucositis among the three agents and in most cases lesions resolved spontaneously. Oral mucositis is a frequent complication of mTOR inhibitor therapy and a significant cause of dose reductions and discontinuations in oncology trials. Prevention and management strategies should be investigated to improve tolerability and better permit effective long-term regimens. © 2012 Elsevier Ltd. All rights reserved.