Nanotechnology: a promising method for oral cancer detection and diagnosis

Oral cancer is a common and aggressive cancer with high morbidity, mortality, and recurrence rate globally. Early detection is of utmost importance for cancer prevention and disease management. Currently, tissue biopsy remains the gold standard for oral cancer diagnosis, but it is invasive, which may cause patient discomfort. The application of traditional noninvasive methods-such as vital staining, exfoliative cytology, and molecular imaging-is limited by insufficient sensitivity and specificity. Thus, there is an urgent need for exploring noninvasive, highly sensitive, and specific diagnostic techniques. Nano detection systems are known as new emerging noninvasive strategies that bring the detection sensitivity of biomarkers to nano-scale. Moreover, compared to current imaging contrast agents, nanoparticles are more biocompatible, easier to synthesize, and able to target specific surface molecules. Nanoparticles generate localized surface plasmon resonances at near-infrared wavelengths, providing higher image contrast and resolution. Therefore, using nano-based techniques can help clinicians to detect and better monitor diseases during different phases of oral malignancy. Here, we review the progress of nanotechnology-based methods in oral cancer detection and diagnosis.

[1]  N. Jokerst,et al.  Flexible silicon sensors for diffuse reflectance spectroscopy of tissue. , 2017, Biomedical optics express.

[2]  K. Chuang,et al.  Magnetic resonance imaging (MRI) contrast agents for tumor diagnosis. , 2013, Journal of healthcare engineering.

[3]  Luigi Laino,et al.  The potential role of in vivo reflectance confocal microscopy for evaluating oral cavity lesions: a systematic review. , 2016, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[4]  Q. Tang,et al.  Theranostic micelles based on upconversion nanoparticles for dual-modality imaging and photodynamic therapy in hepatocellular carcinoma. , 2018, Nanoscale.

[5]  N. Ohuchi,et al.  Quantitative diagnostic imaging of cancer tissues by using phosphor-integrated dots with ultra-high brightness , 2017, Scientific Reports.

[6]  O. Ogle,et al.  Nanotechnology in dentistry today. , 2014, West Indian medical journal.

[7]  Chad A Mirkin,et al.  NanoFlares for the detection, isolation, and culture of live tumor cells from human blood , 2014, Proceedings of the National Academy of Sciences.

[8]  F. Chen,et al.  Diagnostic model of saliva peptide finger print analysis of oral squamous cell carcinoma patients using weak cation exchange magnetic beads , 2015, Bioscience reports.

[9]  J. Bagan,et al.  Utility of imaging techniques in the diagnosis of oral cancer. , 2015, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[10]  Jia Hui Ng,et al.  Changing epidemiology of oral squamous cell carcinoma of the tongue: A global study , 2017, Head & neck.

[11]  Min Soo Bae,et al.  Current Progress in Nanotechnology Applications for Diagnosis and Treatment of Kidney Diseases , 2015, Advanced healthcare materials.

[12]  Jennifer K Barton,et al.  Optical coherence tomography with plasmon resonant nanorods of gold. , 2007, Optics letters.

[13]  T. Salo,et al.  Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis , 2017, British Journal of Cancer.

[14]  R. Ankri,et al.  Diffusion Reflection , 2014, Journal of dental research.

[15]  R. Srivastava,et al.  Magnetic core-shell hybrid nanoparticles for receptor targeted anti-cancer therapy and magnetic resonance imaging. , 2017, Journal of colloid and interface science.

[16]  James F. Rusling,et al.  Multiplex Immunosensor Arrays for Electrochemical Detection of Cancer Biomarker Proteins. , 2016, Electroanalysis.

[17]  J. Conde,et al.  Gold nanostars for efficient in vitro and in vivo real-time SERS detection and drug delivery via plasmonic-tunable Raman/FTIR imaging. , 2016, Biomaterials.

[18]  Kemin Wang,et al.  Immunofluorescent labeling of cancer cells with quantum dots synthesized in aqueous solution. , 2006, Analytical biochemistry.

[19]  Colin Hopper,et al.  Optical diagnostic techniques for use in lesions of the head and neck: review of the latest developments. , 2014, The British journal of oral & maxillofacial surgery.

[20]  R. Chen,et al.  In vivo and in situ imaging of head and neck squamous cell carcinoma using near-infrared fluorescent quantum dot probes conjugated with epidermal growth factor receptor monoclonal antibodies in mice. , 2012, Oncology reports.

[21]  Dean Ho,et al.  Nanodiamonds: The intersection of nanotechnology, drug development, and personalized medicine , 2015, Science Advances.

[22]  D. Pang,et al.  Near-Infrared Fluorescent Ag2 Se-Cetuximab Nanoprobes for Targeted Imaging and Therapy of Cancer. , 2017, Small.

[23]  Daisuke Kokuryo,et al.  Chemical nature and structure of organic coating of quantum dots is crucial for their application in imaging diagnostics , 2011, International journal of nanomedicine.

[24]  Jianfang Wang,et al.  Homogeneous Immunosorbent Assay Based on Single-Particle Enumeration Using Upconversion Nanoparticles for the Sensitive Detection of Cancer Biomarkers. , 2018, Analytical chemistry.

[25]  M. Varvares,et al.  Surgical margins and primary site resection in achieving local control in oral cancer resections , 2015, The Laryngoscope.

[26]  M. Momin,et al.  Oral Squamous Cell Carcinoma: Current Treatment Strategies and Nanotechnology-Based Approaches for Prevention and Therapy. , 2016, Critical reviews in therapeutic drug carrier systems.

[27]  Lauro T Kubota,et al.  InP Nanowire Biosensor with Tailored Biofunctionalization: Ultrasensitive and Highly Selective Disease Biomarker Detection. , 2017, Nano letters.

[28]  S. Warnakulasuriya,et al.  Assessing the accuracy of autofluorescence, chemiluminescence and toluidine blue as diagnostic tools for oral potentially malignant disorders—a clinicopathological evaluation , 2015, Clinical Oral Investigations.

[29]  Jie Pan,et al.  Double labeling and comparison of fluorescence intensity and photostability between quantum dots and FITC in oral tumors. , 2011, Molecular medicine reports.

[30]  R Richards-Kortum,et al.  Optical Systems for in Vivo Molecular Imaging of Cancer , 2003, Technology in cancer research & treatment.

[31]  K. Soo,et al.  Early diagnosis of oral cancer based on the surface plasmon resonance of gold nanoparticles , 2007, International journal of nanomedicine.

[32]  Ping Liu,et al.  A cell-targeted chemotherapeutic nanomedicine strategy for oral squamous cell carcinoma therapy , 2015, Journal of Nanobiotechnology.

[33]  Carolyn L Bayer,et al.  Ultrasound-guided spectral photoacoustic imaging of hemoglobin oxygenation during development. , 2017, Biomedical optics express.

[34]  Wei Huang,et al.  Perylene‐Diimide‐Based Nanoparticles as Highly Efficient Photoacoustic Agents for Deep Brain Tumor Imaging in Living Mice , 2015, Advanced materials.

[35]  W. Moon,et al.  Ultrasound-guided photoacoustic imaging for the selective detection of EGFR-expressing breast cancer and lymph node metastases , 2016, Biomedical optics express.

[36]  P. Jeemon,et al.  Diffuse reflectance spectroscopy: diagnostic accuracy of a non-invasive screening technique for early detection of malignant changes in the oral cavity , 2011, BMJ Open.

[37]  Bharat Sankhla,et al.  A Review of Salivary Biomarker: A Tool for Early Oral Cancer Diagnosis , 2017, Advanced biomedical research.

[38]  J. McDevitt,et al.  Nano-Bio-Chip Sensor Platform for Examination of Oral Exfoliative Cytology , 2010, Cancer Prevention Research.

[39]  Ambika Bumb,et al.  Macromolecules, dendrimers, and nanomaterials in magnetic resonance imaging: the interplay between size, function, and pharmacokinetics. , 2010, Chemical reviews.

[40]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[41]  Jie Pan,et al.  Quantum dot imaging for HSP70 and HSF‑1 kinetics in SCC‑25 cells with or without leucine deprivation following heat shock. , 2013, Oncology reports.

[42]  N. Artzi,et al.  Bioresponsive antisense DNA gold nanobeacons as a hybrid in vivo theranostics platform for the inhibition of cancer cells and metastasis , 2015, Scientific Reports.

[43]  Jianfang Wang,et al.  Shape- and size-dependent refractive index sensitivity of gold nanoparticles. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[44]  Kumar R Saravana,et al.  Nanotechnology in dentistry. , 2006, Indian journal of dental research : official publication of Indian Society for Dental Research.

[45]  S. Nair,et al.  Highly biocompatible TiO₂:Gd³⁺ nano-contrast agent with enhanced longitudinal relaxivity for targeted cancer imaging. , 2011, Nanoscale.

[46]  K. Pantel,et al.  Squamous cell carcinoma of the oral cavity and circulating tumour cells. , 2014, World journal of clinical oncology.

[47]  M. El-Sayed,et al.  Some interesting properties of metals confined in time and nanometer space of different shapes. , 2001, Accounts of chemical research.

[48]  Nitin A. Pagedar,et al.  Definition of “Close Margin” in Oral Cancer Surgery and Association of Margin Distance With Local Recurrence Rate , 2017, JAMA otolaryngology-- head & neck surgery.

[49]  Michele Follen,et al.  Real-time vital optical imaging of precancer using anti-epidermal growth factor receptor antibodies conjugated to gold nanoparticles. , 2003, Cancer research.

[50]  Khadijah Mohideen,et al.  Autofluorescence based diagnostic techniques for oral cancer , 2015, Journal of pharmacy & bioallied sciences.

[51]  Igor L. Medintz,et al.  Quantum dot bioconjugates for imaging, labelling and sensing , 2005, Nature materials.

[52]  Ravindran Girija Aswathy,et al.  Near-infrared quantum dots for deep tissue imaging , 2010, Analytical and bioanalytical chemistry.

[53]  Takuji Tanaka,et al.  Understanding Carcinogenesis for Fighting Oral Cancer , 2011, Journal of oncology.

[54]  Z. Khan,et al.  Smokeless Tobacco and Oral Potentially Malignant Disorders in South Asia: A Systematic Review and Meta-analysis , 2016, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[55]  C. Farah,et al.  Oral mucosal disease in an Australian urban Indigenous community using autofluorescence imaging and reflectance spectroscopy. , 2015, Australian dental journal.

[56]  P. Vescovi,et al.  Non-invasive visual tools for diagnosis of oral cancer and dysplasia: A systematic review , 2016, Medicina oral, patologia oral y cirugia bucal.

[57]  A. Nassar,et al.  Rapid label‐free profiling of oral cancer biomarker proteins using nano‐UPLC‐Q‐TOF ion mobility mass spectrometry , 2016, Proteomics. Clinical applications.

[58]  Kai Yang,et al.  Quantum dot-based visual in vivo imaging for oral squamous cell carcinoma in mice. , 2010, Oral oncology.

[59]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[60]  Ya-Qin Tan,et al.  Meta-analysis of two computer-assisted screening methods for diagnosing oral precancer and cancer. , 2015, Oral oncology.

[61]  G. Campisi,et al.  Novel non-invasive adjunctive techniques for early oral cancer diagnosis and oral lesions examination. , 2012, Current pharmaceutical design.

[62]  Yuyan Jiang,et al.  Advanced Photoacoustic Imaging Applications of Near-Infrared Absorbing Organic Nanoparticles. , 2017, Small.

[63]  G. Liang,et al.  Quantum Dots as Multifunctional Materials for Tumor Imaging and Therapy , 2013, Materials.

[64]  Michael Schmidt,et al.  Structural-mechanical characterization of nanoparticle exosomes in human saliva, using correlative AFM, FESEM, and force spectroscopy. , 2010, ACS nano.

[65]  J. Sekine,et al.  Diagnostic accuracy of oral cancer cytology in a pilot study , 2017, Diagnostic Pathology.

[66]  Dror Fixler,et al.  Gold Nanorods Based Air Scanning Electron Microscopy and Diffusion Reflection Imaging for Mapping Tumor Margins in Squamous Cell Carcinoma. , 2016, ACS nano.

[67]  Z. Khurshid,et al.  Advances of Salivary Proteomics in Oral Squamous Cell Carcinoma (OSCC) Detection: An Update , 2016, Proteomes.

[68]  Jerry C. Chang,et al.  Biocompatible quantum dots for biological applications. , 2011, Chemistry & biology.

[69]  Konstantin V Sokolov,et al.  Sentinel lymph node biopsy revisited: ultrasound-guided photoacoustic detection of micrometastases using molecularly targeted plasmonic nanosensors. , 2014, Cancer research.

[70]  H. Shinmoto,et al.  Pilot Study of Prostate Cancer Angiogenesis Imaging Using a Photoacoustic Imaging System. , 2017, Urology.

[71]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[72]  P. Chu,et al.  Bimodal optical diagnostics of oral cancer based on Rose Bengal conjugated gold nanorod platform. , 2013, Biomaterials.

[73]  Adam K Glaser,et al.  Raman-Encoded Molecular Imaging with Topically Applied SERS Nanoparticles for Intraoperative Guidance of Lumpectomy. , 2017, Cancer research.

[74]  N. Artzi,et al.  Implantable hydrogel embedded dark-gold nanoswitch as a theranostic probe to sense and overcome cancer multidrug resistance , 2015, Proceedings of the National Academy of Sciences.

[75]  P. Chandrasekharan,et al.  Octreotide Functionalized Nano-Contrast Agent for Targeted Magnetic Resonance Imaging. , 2016, Biomacromolecules.

[76]  Automated analysis of multimodal fluorescence lifetime imaging and optical coherence tomography data for the diagnosis of oral cancer in the hamster cheek pouch model , 2016, Biomedical optics express.

[77]  P. Couvreur,et al.  Nanoparticles in cancer therapy and diagnosis. , 2002, Advanced drug delivery reviews.

[78]  H. Mirzaei,et al.  Molecular Imaging and Oral Cancer Diagnosis and Therapy , 2017, Journal of cellular biochemistry.

[79]  P. Kämmerer,et al.  A chemiluminescent light system in combination with toluidine blue to assess suspicious oral lesions—clinical evaluation and review of the literature , 2014, Clinical Oral Investigations.

[80]  Zhongpin Zhang,et al.  Click-Functionalized SERS Nanoprobes with Improved Labeling Efficiency and Capability for Cancer Cell Imaging. , 2017, ACS applied materials & interfaces.

[81]  P. Brennan,et al.  Oral submucous fibrosis: An update on pathophysiology of malignant transformation , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[82]  Peter T C So,et al.  High resolution live cell Raman imaging using subcellular organelle-targeting SERS-sensitive gold nanoparticles with highly narrow intra-nanogap. , 2015, Nano letters.

[83]  G. Meng,et al.  Long-range surface plasmon resonance and surface-enhanced Raman scattering on X-shaped gold plasmonic nanohole arrays. , 2017, Physical chemistry chemical physics : PCCP.

[84]  R H Hruban,et al.  Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. , 1995, The New England journal of medicine.

[85]  H. Zeng,et al.  Pilot study: Raman spectroscopy in differentiating premalignant and malignant oral lesions from normal mucosa and benign lesions in humans , 2015, Head & neck.

[86]  Seungah Lee,et al.  Ultra-sensitive detection of tumor necrosis factor-alpha on gold nano-patterned protein chip formed via E-beam nanolithography by total internal reflection fluorescence microscopy. , 2010, Journal of nanoscience and nanotechnology.

[87]  Luigi Laino,et al.  The potential role of in vivo optical coherence tomography for evaluating oral soft tissue: A systematic review , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[88]  Scott C. Brown,et al.  Nanoparticles for bioimaging. , 2006, Advances in colloid and interface science.

[89]  N. Saba,et al.  Oral Cavity Cancer: Risk Factors, Pathology, and Management , 2015, Oncology.

[90]  Sarah E Bohndiek,et al.  Contrast agents for molecular photoacoustic imaging , 2016, Nature Methods.

[91]  E. N. Lebedenko,et al.  Quantum Dots for Molecular Diagnostics of Tumors , 2011, Acta Naturae.

[92]  J. Conde,et al.  Gold nanoprisms as a hybrid in vivo cancer theranostic platform for in situ photoacoustic imaging, angiography, and localized hyperthermia , 2016, Nano Research.

[93]  Xiaohua Huang,et al.  Surface plasmon resonance scattering and absorption of anti-EGFR antibody conjugated gold nanoparticles in cancer diagnostics: applications in oral cancer. , 2005, Nano letters.

[94]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[95]  Chao Li,et al.  CD44v6 Monoclonal Antibody-Conjugated Gold Nanostars for Targeted Photoacoustic Imaging and Plasmonic Photothermal Therapy of Gastric Cancer Stem-like Cells , 2015, Theranostics.

[96]  P. Brennan,et al.  Optical diagnostic systems for assessing head and neck lesions. , 2016, Oral diseases.

[97]  P. Jeemon,et al.  Diagnostic accuracy of diffuse reflectance imaging for early detection of pre-malignant and malignant changes in the oral cavity: a feasibility study , 2013, BMC Cancer.

[98]  Young Soo Park,et al.  Measurements of serum C-reactive protein levels in patients with gastric cancer and quantification using silicon nanowire arrays. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[99]  Amy L Oldenburg,et al.  Plasmon-resonant gold nanorods as low backscattering albedo contrast agents for optical coherence tomography. , 2006, Optics express.

[100]  Zhongping Chen,et al.  Enhanced detection of early-stage oral cancer in vivo by optical coherence tomography using multimodal delivery of gold nanoparticles. , 2009, Journal of biomedical optics.

[101]  Bo Li,et al.  Label-free blood serum detection by using surface-enhanced Raman spectroscopy and support vector machine for the preoperative diagnosis of parotid gland tumors , 2015, BMC Cancer.

[102]  Jae-Hong Kim,et al.  Dual-Color Emissive Upconversion Nanocapsules for Differential Cancer Bioimaging In Vivo. , 2016, ACS nano.

[103]  J. Hoxworth,et al.  Margin mapping in transoral surgery for head and neck cancer , 2013, The Laryngoscope.

[104]  W. Kuo,et al.  Diagnostic model of saliva peptide finger print analysis of primary Sjögren's syndrome patients by using weak cation exchange magnetic beads , 2013, Bioscience reports.

[105]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[106]  Daxiang Cui,et al.  Antibody-drug gold nanoantennas with Raman spectroscopic fingerprints for in vivo tumour theranostics. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[107]  J. Matthew Mauro,et al.  Long-term multiple color imaging of live cells using quantum dot bioconjugates , 2003, Nature Biotechnology.

[108]  K. Bennett,et al.  MR imaging techniques for nano-pathophysiology and theranostics. , 2014, Advanced drug delivery reviews.

[109]  P. Nicolai,et al.  The diagnostic value of narrow band imaging in different oral and oropharyngeal subsites , 2016, European Archives of Oto-Rhino-Laryngology.

[110]  W. Cai,et al.  Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy. , 2018, Biomaterials.

[111]  Xiaoxin L Chen,et al.  Quantitative prediction of oral cancer risk in patients with oral leukoplakia , 2017, Oncotarget.

[112]  Kai Yang,et al.  Optical imaging of head and neck squamous cell carcinoma in vivo using arginine-glycine-aspartic acid peptide conjugated near-infrared quantum dots , 2013, OncoTargets and therapy.

[113]  I. Rehman,et al.  Raman spectroscopy can discriminate between normal, dysplastic and cancerous oral mucosa: a tissue‐engineering approach , 2017, Journal of tissue engineering and regenerative medicine.

[114]  R. Ankri,et al.  Gold nanorods reflectance discriminate benign from malignant oral lesions. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[115]  Chad A Mirkin,et al.  Multiplexed nanoflares: mRNA detection in live cells. , 2012, Analytical chemistry.

[116]  Chang-Seok Kim,et al.  In vivo photoacoustic monitoring using 700-nm region Raman source for targeting Prussian blue nanoparticles in mouse tumor model , 2018, Scientific Reports.

[117]  Chao Jiang,et al.  Progesterone inhibits inflammatory response pathways after permanent middle cerebral artery occlusion in rats. , 2011, Molecular medicine reports.

[118]  J. Epstein,et al.  Toluidine blue aids in detection of dysplasia and carcinoma in suspicious oral lesions. , 2015, Oral diseases.

[119]  Chen Chen,et al.  Recovering the superficial microvascular pattern via diffuse reflection imaging: phantom validation , 2015, BioMedical Engineering OnLine.

[120]  Ahmed Raheem,et al.  Accuracy of frozen sections in oral cancer resections, an experience of a tertiary care hospital. , 2017, JPMA. The Journal of the Pakistan Medical Association.

[121]  Qianming Chen,et al.  Non-Invasive Techniques for Detection and Diagnosis of Oral Potentially Malignant Disorders. , 2016, The Tohoku journal of experimental medicine.

[122]  Marlus Chorilli,et al.  Nanotechnology-based drug delivery systems for treatment of oral cancer: a review , 2014, International journal of nanomedicine.

[123]  E. Omar Future Imaging Alternatives: The Clinical Non-invasive Modalities in Diagnosis of Oral Squamous Cell Carcinoma (OSCC) , 2015, The open dentistry journal.

[124]  D. Ramaiah,et al.  Unveiling NIR Aza-Boron-Dipyrromethene (BODIPY) Dyes as Raman Probes: Surface-Enhanced Raman Scattering (SERS)-Guided Selective Detection and Imaging of Human Cancer Cells. , 2017, Chemistry.

[125]  Jaehong Key,et al.  Positron emitting magnetic nanoconstructs for PET/MR imaging. , 2014, Small.

[126]  A. Starzyńska,et al.  Contemporary Diagnostic Imaging of Oral Squamous Cell Carcinoma – A Review of Literature , 2017, Polish journal of radiology.

[127]  Hao Huang,et al.  Paper-based plasmonic platform for sensitive, noninvasive, and rapid cancer screening. , 2014, Biosensors & bioelectronics.

[128]  S. Warnakulasuriya Global epidemiology of oral and oropharyngeal cancer. , 2009, Oral oncology.

[129]  P. Holloway,et al.  Quantum Dots and Their Multimodal Applications: A Review , 2010, Materials.

[130]  V. Jaishree,et al.  Nanotechnology: A Revolution in Cancer Diagnosis , 2012, Indian Journal of Clinical Biochemistry.

[131]  L. Kong,et al.  EMMPRIN contributes to the in vitro invasion of human salivary adenoid cystic carcinoma cells , 2011, Oncology reports.

[132]  Matthew A Wall,et al.  Cancer imaging using surface-enhanced resonance Raman scattering nanoparticles , 2017, Nature Protocols.

[133]  James F Rusling,et al.  Ultrasensitive detection of cancer biomarkers in the clinic by use of a nanostructured microfluidic array. , 2012, Analytical chemistry.

[134]  Laurence J. Hardwick,et al.  Shell isolated nanoparticles for enhanced Raman spectroscopy studies in lithium-oxygen cells. , 2017, Faraday discussions.

[135]  Kai Yang,et al.  In-vivo imaging of oral squamous cell carcinoma by EGFR monoclonal antibody conjugated near-infrared quantum dots in mice , 2011, International journal of nanomedicine.

[136]  D. Torres-Lagares,et al.  The role of serum biomarkers in the diagnosis and prognosis of oral cancer: A systematic review , 2016, Journal of clinical and experimental dentistry.

[137]  Rebecca L. Siegel Mph,et al.  Cancer statistics, 2016 , 2016 .