Introduction
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Toluidine blue
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Oral brush biopsy
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Conventional oral brush biopsy
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Oral brush biopsy coupled with computer-assisted analysis
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Saliva-Based Oral Cancer Diagnosis
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Genomic substances
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Transcriptomc substances
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Proteomic substances
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Light-based detection systems:
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Chemiluminescence (ViziLite Plus; Microlux/DL, Orascoptic-DK)
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Tissue fluorescence imaging (VELscope)
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Optical Biopsy:
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Tissue fluorescence spectroscopy
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Raman spectroscopy
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Elastic scattering Spectroscopy
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Differential path-length spectroscopy
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Nuclear magnetic resonance spectroscopy
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Confocal reflectance microscopy (CRM)
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Optical Coherence Tomography
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Angle-resolved low coherence interferometry (A/LCI)
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Others
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Biomarkers:
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DNA-analysis
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Laser capture microdissection
Methods
Key questions
Data sources and selection of articles for possible inclusion
Set | Concept | Search statement |
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1 | Oral | Oral cavity |
2 | Oral biopsy | Surgical biopsy, Toluidine blue staining, Oral brush biopsy, Optical Biopsy |
3 | Optical Biopsy | Fluorescence spectroscopy, Raman spectroscopy, Elastic scattering spectroscopy, Differential path-length spectroscopy, Optical Tomography |
4 | Fluorescence spectroscopy | Auto-fluorescence spectroscopy, Enhanced dye fluorescence, Ratio imaging |
5 | Oral diseases | Tumors, carcinoma |
6 | Combined set | 2, 5 |
7 | Combined set | 3, 5 |
8 | Combined set | 3, 4, 5 |
9 | Saliva | Saliva-based oral cancer diagnosis, |
10 | Oral Saliva changes in cancer patients | Genomic substance, Transcriptomic mRNA, Proteomic substances |
11 | Combined set | 9, 10 |
12 | Combined set | 6, 7, 8, 11 |
13 | Limit by publication type | 5,6, 8, 11, 12: Not letter or editorial or news or comments or case report or notes or conference paper |
14 | Diagnostics filter | 13 and (predictive value of tests or sensitivity and specificity or accuracy or diagnostic accuracy or precision or likelihood) or (false or true) or (positive or negative) |
15 | Clinical trials filter | 14 and (Randomized controlled trials or random allocation or double-blind method or single-blind method or cross-over studies or crossover procedure or double blind procedure or single blind procedure or crossover design or double-blind studies or single-blind studies or triple-blind studies or random assignment or exp controlled study/or exp clinical trial/or exp comparative study or intermethod comparison or parallel design or control group or prospective study or case control study or major clinical study) or Case control studies/or Cohort/or Longitudinal studies/or Evaluation studies/or Prospective studies |
16 | Combined set | 14, 15 |
17 | Patient satisfaction | 13 and (patient satisfaction or pain measurement or pain assessment or visual analog scale or quality of life). |
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Toluidine blue staining,
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Oral brush biopsy,
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Optical Biopsy
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Fluorescence spectroscopy,
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Raman spectroscopy,
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Elastic scattering spectroscopy,
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Differential path-length spectroscopy,
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Optical Tomography
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Nuclear magnetic resonance spectroscopy
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Enhanced dye fluorescence,
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Ratio imaging
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Saliva-based oral cancer diagnosis
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Genomic substance,
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Trans-criptomic mRNA,
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Proteomic substances
Data abstraction and quality assessment
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Category 1: Spectrum composition
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Was the spectrum of patients described in the paper and was it chosen adequately?
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Were selection criteria described clearly?
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Was the method of population recruitment consecutive?
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Was the setting of the study relevant?
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Was disease prevalence and severity reported? (not included in QUADAS)
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Category 2a: Index test and reference standard: Selection and execution
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In light of current technology, was the reference standard chosen appropriate to verify test results?
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Is it possible that a change in the technology of the index test has occurred since this paper was published? (not included in QUADAS)
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Was there an abnormally long time period between the performance of the test under evaluation and the confirmation of the diagnosis with the reference standard?
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Was the execution of the index test described in sufficient detail to permit replication of the test?
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Was the execution of the reference standard described in sufficient detail to permit replication of the test?
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Did the whole sample, or a random selection of the sample, receive verification using a reference standard of diagnosis?
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Did all patients receive the same reference standard regardless of the index test result?
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Were the results of the index test incorporated in the results of the reference standard?
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Was the cut-off value pre-specified or acceptable in light of previous research? (not included in QUADAS)
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Was treatment started based on the knowledge of the index test results before the reference standard was applied? (not included in QUADAS)
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Category 2b: Index test and reference standard: Interpretation
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Were the index test results interpreted blind to the results of the reference standard?
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Were the reference standard results interpreted blind to the results of the index test?
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Was clinical data available when test results were interpreted?
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Is data presented on observer or instrument variation that could have affected the estimates of test performance? (not included in QUADAS)
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Category 3: Analysis
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Were appropriate results presented (sensitivity, specificity, likelihood ratios, diagnostic odds ratios, predictive values) and were these calculated appropriately? (not included in QUADAS)
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Was a measure of precision of the results presented (confidence intervals, standard errors)? (not included in QUADAS)
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Were uninterpretable/indeterminate/ intermediate results reported and included in the results?
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Was the threshold value specified retrospectively based on analysis of the results? (not included in QUADAS)
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Were reasons for drop-out from the study reported?
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Were subgroup analyses pre-specified and clinically relevant? (not included in QUADAS)
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Were results presented in a 2 × 2 data table? (not included in QUADAS)
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Was any indication of the utility of the test provided? (not included in QUADAS)
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Category 4: Research Planning
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Was an appropriate sample size calculation performed and were sufficient patients included in the study? (not included in QUADAS)
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Were study objectives clearly reported? (not included in QUADAS)
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Was there any evidence that a study protocol had been developed before the study was started? (not included in QUADAS)
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Statistical analysis
Results
Evidence of validity of non-invasive methods in diagnosing OSCC
Study | Study or biopsy type(s) | Quality score | Type of study | Care setting | Country conducted in | Funded by | Number of patients enrolled |
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Epstein et al. 1997 [10] | Toluidine blue | 7 | Prospective | Department of Dentistry, British Columbia Cancer Agency | Canada | British Columbia Cancer Agency | - |
Bouquot et al. 1986 [11] | Toluidine blue | 6.5 | Prospective | - | USA | - | 23,616 |
Martin et al. 1998 [23] | Toluidine blue | 6.3 | - | Department of Oral and Facial Surgery, Sunderland Royal Hospital | UK | - | - |
Scheifele et al. 2004 [24] | OralCDx® technique | 6.4 | Prospective | Department of Oral Surgery and Dental Radiology, Zentrum für Zahnmedizin, Campus Virchow, Charité--Universitätsmedizin Berlin | Germany | - | 103 |
Sciubba 1999 [26] | OralCDx® technique | 7.3 | Prospective | Department of Dental Medicine, Long Island Jewish Medical Center | USA | U.S. Collaborative OralCDx® Study Group | 945 |
Gupta et al. 2007 [26] | Oral brush biopsy | 5.8 | Prospective | Department of Pathology, Moti Lal Nehru Medical College, Allahabad University | India | - | 96 |
Poate et al. 2004 [28] | Oral brush biopsy | 7.5 | Prospective | Oral Medicine, Division of Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman Dental Institute for Oral Health Care Sciences | UK | - | 112 |
Weigum et al. 2010 [29] | Nanobiochip, exfoliative cytology | 7.7 | Prospective | Department of Dental Diagnostic Science, University of Texas Health Science Center | USA | National Institute for Dental and Craniofacial Research | 52 |
Jokerst et al. 2010 [31] | Nanobiochip | 6.6 | Prospective | Stanford University School of Medicine | USA | - | - |
Wei et al. 2009 [32] | Saliva biomarkers | 7.5 | Prospective | University of California, Los Angeles School of Dentistry and Dental Research Institute | USA | NIH/National Institute of Dental and Craniofacial Research | - |
Floriano et al. 2009 [33] | Saliva-based nanobiochip tests | 7.6 | Prospective | Department of Chemistry and Biochemistry, University of Texas | USA | National Institute of Dental and Craniofacial Research | 41 |
Liu et al. 2009 [34] | Saliva biomarkers | 7.5 | Prospective | Department of Mechanical Engineering and Applied Mechanics, | USA | University of Pennsylvania Institute for Translational Medicine and Therapeutics | - |
Zimmermann et al. 2007 [36] | Saliva biomarkers | 7.8 | Prospective | School of Dentistry and Dental Research Institute, University of California | USA | National Institute of Health | - |
Xie et al. 2008 [37] | Saliva biomarkers | 7 | Prospective | Department of Biochemistry, Molecular Biology, and Biophysics, School of Dentistry, University of Minnesota | USA | - | - |
Sugimoto et al. 2010 [39] | Saliva biomarkers | 8 | Prospective | UCLA Medical Center | USA | National Institute of Health | 215 |
Hu et al. 2008 [41] | Saliva biomarkers | 7.6 | Prospective | Oral Biology and Medicine Division and Dental Research Institute, School of Dentistry, University of California | USA | U.S. Public Health Service | 64 |
Rosin et al. 2000 [44] | Biomarkers; genetic | 7.7 | Prospective | British Columbia Cancer Agency/Cancer Research Centre | Canada | National Cancer Institute of Canada, Canadian Cancer Society | 116 |
Boyle et al. 1993 [48] | Biomarkers; genetic | 7.6 | Prospective | Department of Oral Surgery, Johns Hopkins University | USA | - | 102 |
Rosas et al. 2001 [50] | Biomarkers; genetic | 7.9 | Prospective | Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine | USA | National Institute of Dental and Craniofacial Research (NIH) | 30 |
Chien et al. 1990 [52] | Biomarkers; genetic | 7.5 | Prospective | Department of Obstetrics and Gynaecology, First Affiliated Hospital, Human Medical University | China | - | 92 |
Handschel et al. 2007 [54] | Biomarkers; genetic | 6.9 | Prospective | Department for Cranio- and Maxillofacial Surgery, Heinrich-Heine-University | Germany | - | - |
Hasselmann et al. 2001 [55] | Saliva biomarkers; clinical chemistry | 6.4 | Prospective | Department of Dermatology, Saarland University Hospital | Germany | - | - |
Ratajczak et al. 2006 [56] | Biomarkers; cellular | 7.2 | Prospective | James Graham Brown Cancer Center, University of Louisville | USA | Stem Cell Biology Program | - |
García et al. 2008 [57] | Biomarkers; genetic | 7.5 | Prospective | Department of Medical Oncology, Hospital Universitario Puerta de Hierro | Spain | Ministerio de Educación y Ciencia and the Fundación de Investigación Médica Mutua Madrileña | - |
Skog et al. 2008 [59] | Biomarkers; genetic | 7.5 | Prospective | Department of Neurology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School | USA | Wenner-Gren Foundation Stiftelsen Olle Engkvist Byggmästare, Brain Tumor Society, and American Brain Tumor Association | - |
Shpitzer et al. 2009 [63] | Saliva biomarkers | 7.8 | Prospective | Department of Otorhinolaryngology, Rabin Medical Center, Petah Tiqva and Sackler Faculty of Medicine | - | - | 19 |
Vairaktaris et al. 2008 [64] | Saliva biomarkers | 7.5 | Prospective | Department of Oral and Maxillofacial Surgery, University of Athens Medical School, Attikon Hospital | Greece | - | 152 |
St John et al. 2004 [64] | Saliva biomarkers | 7.7 | Prospective | School of Medicine, UCLA | USA | National Institutes of Health, UCLA Jonsson Cancer Center | 32 |
Rhodus et al. 2005 [66] | Saliva biomarkers | 7.6 | Prospective | Department of Oral Medicine, University of Minnesota | USA | - | 13 |
Arellano-Garcia et al. 2008 [67] | Saliva biomarkers | 7.5 | Prospective | School of Dentistry, Oral Biology and Medicine Division, Dental Research Institute, University of California | USA | U.S. Public Health Service | 19 |
Betz et al. 2002 [111] | Optical biopsy | 7.9 | Prospective | Department of Oto-Rhino-Laryngology/Head and Neck Surgery, Ludwig Maximilians University | Germany | Wilhelm Sander Foundation | 85 |
Leunig et al. 2000 [112] | Optical biopsy | 7.5 | Prospective | Department of Otorhinolaryngology--Head and Neck Surgery, University of Munich | Germany | Wilhelm Sander Foundation | 8 |
Betz et al. 1999 [101] | Optical biopsy | 7.7 | Prospective | Department of Oto-Rhino-Laryngology/Head & Neck Surgery, Ludwig Maximilian University | Germany | Wilhelm Sander Foundation | 49 |
Kulbersh et al. 2007 [103] | Optical biopsy | 7.5 | Prospective | Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alabama | USA | American Cancer Society, University of Alabama at Birmingham Comprehensive Cancer Center Core Grant NIH | 33 Models |
Ebenezar et al. 2012 [113] | Optical biopsy | 7.3 | Prospective | Anna University, Department of Medical Physics | India | - | 25 |
Duraipandian et al. 2012 [118] | Optical biopsy | 7.8 | Prospective | National University of Singapore, Department of Bioengineering, Faculty of Engineering, Optical Bioimaging Laboratory | Singapore | National University of Singapore | 2748 |
Guze et al. 2014 [133] | Optical biopsy | 7.8 | Prospective | Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Divisions of Oral Medicine, Dana-Farber Cancer Institute and Brigham and Women’s Hospital | USA | - | 18 |
Krishnakumar et al. 2013 [125] | Optical biopsy | 7.5 | Prospective | Department of Physics, Annamalai University | India | - | - |
Sahu et al. 2013 [126] | Optical biopsy | 7 | - | Chilakapati lab, ACTREC, Tata Memorial Centre | India | Advanced Centre for Treatment Research and Education in Cancer | 70 |
Singh et al. 2013 [128] | Optical biopsy | 7.3 | Prospective | Chilakapati lab, ACTREC, Tata Memorial Centre | India | Advanced Centre for Treatment Research and Education in Cancer | 84 |
Singh et al. 2012 [127] | Optical biopsy | 7.5 | Prospective | Advanced Centre for Treatment Research and Education in Cancer, Chilakapati Laboratory | India | Advanced Centre for Treatment Research and Education in Cancer | 104 subjects |
Deshmukh et al. 2011 [129] | Optical biopsy | 7 | Prospective | Chilakapati Laboratory | India | Advanced Center for Treatment Research and Education in Cancer | 10 |
Oliveira et al. 2006 [130] | Optical biopsy | 7.2 | Prospective | Grupo de Optica Biomédica, Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraíba | Brazil | - | 123 spectra |
Malini et al. 2006 [131] | Optical biopsy | 7.5 | Prospective | Center for Laser Spectroscopy, Manipal Academy of Higher Education | India | Government of India | 216 spectra |
Krishna et al. 2004 [132] | Optical biopsy | 6.8 | Prospective | Center for Laser Spectroscopy, Manipal Academy of Higher Education | India | Government of India | - |
Jerjes et al. 2004 [135] | Optical biopsy | 7.5 | Prospective | Department of Oral and Maxillofacial Surgery, University College London Hospitals | UK | Eastman Dental Institute, UCL, UCLH Head and Neck Centre | 13 |
Sharwani et al. 2006 [140] | Optical biopsy | 7.6 | Prospective | Oral and Maxillofacial Surgery, Eastman Dental Institute | UK | Eastman Dental Institute, UCL, UCLH Head and Neck Centre, London, UK | 25 |
Mourant et al. 2000 [137] | Optical biopsy | 7 | Prospective | Los Alamos National Laboratory, Bioscience Division | USA | - | - |
Mourant et al. 1998 [138] | Optical biopsy | 7.2 | Prospective | Chemical Sciences and Technology Division, Los Alamos National Laboratory | USA | - | - |
Lovat et al. 2006 [139] | Optical biopsy | 7.8 | Prospective | National Medical Laser Centre, Department of Surgery, Royal Free and University College Medical School, University College | UK | National Cancer Institute | 181 |
A’Amar et al. 2013 [144] | Optical biopsy | 7.5 | Prospective | Department of Biomedical Engineering, Boston University | USA | - | 42 |
Denkçeken et al. 2013 [145] | Optical biopsy | 6.9 | Prospective | Biomedical Optics Research Unit, Department of Biophysics, Faculty of Medicine, Akdeniz University | Turkey | Biomedical Optics Research Unit | 10 |
Qi et al. 2012 [143] | Optical biopsy | 7.7 | Prospective | Department of Surgery and Cancer, Imperial College London | UK | ERC grant (China Scholarship Council) | - |
Upile et al. 2012 [142] | Optical biopsy | 7.8 | Prospective | Head & Neck Unit, University College London Hospitals | UK | Eastman Dental Institute, UCL, UCLH Head and Neck Centre | 73 |
Canpolat et al. 2012 [141] | Optical biopsy | 7.6 | Prospective | Department of Biophysics, School of Medicine, Akdeniz University | Turkey | - | 28 |
Lau et al. 2009 [146] | Optical biopsy | 7.9 | Prospective | Massachusetts Institute of Technology, George R. Harrison Spectroscopy Laboratory | USA | National Institutes of Health | - |
Müller et al. 2003 [136] | Optical biopsy | 7.9 | Prospective | Massachusetts Institute of Technology | USA | National Institutes of Health | 91 tissue sites from 15 patients |
Amelink et al. 2004 [147] | Optical biopsy | 7.5 | Prospective | Department of Radiation Oncology, Erasmus Medical Centre | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | - |
Sterenborg et al. 2009 [148] | Study type(s) or biopsy | 7.6 | Prospective | Center for Optical Diagnostics and Therapy, Erasmus Medical Centre | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | 21 |
de Visscher et al. 2012 [150] | Study type(s) or biopsy | 7.5 | Prospective | University Medical Centre Groningen, Department of Oral and Maxillofacial Surgery, Division of Oncology | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | 54 male Wistar rats |
Amelink et al. 2011 [149] | 7.7 | Prospective | Centre for Optical Diagnostics and Therapy, Department of Radiation Oncology, Erasmus Medical Centre | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | 18 | |
Karakullukcu et al. 2011 [151] | Study type(s) or biopsy | 7.6 | Prospective | The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Department of Head and Neck Oncology and Surgery | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | - |
Kanick et al. 2008 [152] | Study type(s) or biopsy | 7.5 | Prospective | Erasmus Medical Centre, Department of Radiation Oncology, Centre for Optical Diagnostics and Therapy | The Netherlands | Dutch Technology Foundation STW, Applied Science Division of NWO and the Technology Program of the Ministry of Economic Affairs | - |
Adalsteinsson et al. 1998 [174] | Study type(s) or biopsy | 7.5 | Prospective | Department of Radiology, Stanford University | USA | - | 12 |
El-Sayed et al. 2002 [175] | Study type(s) or biopsy | 7.8 | Prospective | Cancer Care Manitoba | Canada | Cancer Care Manitoba | 135 |
Maheshwari et al. 2000 [176] | Study type(s) or biopsy | 7.6 | Prospective | Department of Radiology, University of North Carolina | USA | University of North Carolina | 37 |
Mukherji et al. 1997 [177] | Study type(s) or biopsy | 7.8 | Prospective | Department of Radiology, University of North Carolina School of Medicine | USA | - | 49 |
Kunkel et al. 2003 [178] | Biochemical | 7.8 | Prospective | Department of Oral and Maxillofacial Surgery, University Hospital Mainz | Germany | - | 118 |
Selected important study quality items
TB staining
Oral brush biopsy
Saliva-based oral cancer diagnosis
Genomic substances
Genome | Functions | Type of abnormality | Reported rate in the saliva |
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Mitochondrial DNA | mutations | 67% | |
p53 gene: Tumor-suppressor genes | Cell-cycle regulation Senescence, cell-cycle progression | mutations | 71% |
p16* : Tumor-suppressor genes | Cell-cycle regulation Senescence, cell-cycle progression | Hypermethylation | 47% |
DAP-K* | kinase whose expression is required for IFN-γ-induced apoptosis | Hypermethylation | 33% |
MGMT* | Hypermethylation | 23% | |
CDKN2A | Control of cell cycle, arrest cell cycle at G1& G2act like a Tumor-suppressor genes | Hypermethylation | 30.2% |
CDH1 | Encodes Ca++ dependent cell to cell adhesions | Hypermethylation | - |
c-MYCIN: Proto-oncogenes | Cell growth, apoptosis | amplification | 20-40% |
Cyclin D oncogenes: Proto-oncogenes | Cell-cycle regulation | amplification | 87% |
Transcriptomic mRNA
Biomarker | Gene functions | Mean fold increase | Sensitivity (%) | Specificity (%) |
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DUSP1
| Protein modification; signal transduction; oxidative stress | 2.60 | 59 | 75 |
H3F3A
| DNA binding activity | 5.61 | 53 | 81 |
IL1B
| Signal transduction; proliferation; inflammation; apoptosis | 5.48 | 63 | 72 |
IL8
| Angiogenesis; replication; calcium-mediated signaling pathway; cell adhesion; chemotaxis; cell cycle arrest; immune response | 24.3 | 88 | 81 |
OAZ1
| Polyamine biosynthesis | 2.82 | 100 | 38 |
S100P
| Protein binding; calcium ion binding | 4.88 | 72 | 63 |
SAT
| Enzyme, transferase activity | 2.98 | 81 | 56 |
Proteomic substances
Parameter | % Of change | Sensitivity (%) | Specificity (%) |
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Matrix metalloproreinases-9 (MMP-9) | 39 | 100 | 79 |
Salivary Carbonyls | 246 | 90 | 80 |
8-oxoguanine DNA glycosylase (OGG1) | -16 | 77 | 75 |
phospho-Src | -24 | 77 | 75 |
Ki67 | 127 | 58 | 67 |
Maspin | -29 | 100 | 100 |
lactate dehydrogenase (LDH) | 86 | 79 | 42 |
CycD1 | 87 | 100 | 100 |
Light-based systems
Optical biopsy
Autofluorescence imaging
Fluorescence spectroscopy
Autofluorescence spectroscopy
Enhanced dye fluorescence
Ratio imaging
Raman spectroscopy
Elastic scattering spectroscopy
Differential path-length spectroscopy
Optical tomography
Optical coherence tomography
Angle-resolved low coherence interferometry
Nuclear magnetic resonance spectroscopy (NMR)
Infrared spectroscopy
Optical biopsy | Technology | Light source | Information provided | Sensitivity % | Specificity % |
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Auto-fluorescence spectroscopy | Fluorochromes fluorescence (NAD, FADH) | ultraviolet and visible spectrum light | Distinguish malignant tissue by concentration of (NAD, FADH), re-emit green light | 81 | 100 |
Enhanced dye fluorescence | Fluorochromes fluorescence (protoporphyrin IX) | ultraviolet and visible spectrum light | Distinguish malignant tissue by high concentration of (protoporphyrin IX), re-emit red light | 100 | 100 |
Ratio imaging | fluorescence (protoporphyrin IX, NAD, FADH) | ultraviolet and visible blue light | Compare a ratio of red emission of (protoporphyrin IX) from malignant cells with the green emission from normal | from 60 to 97 | from 75 to 99% |
Raman spectroscopy | Raman vibrational spectroscopy | laser-based spectroscopic technique | enabling chemical characterization | 80.5 | 86.2 |
Elastic scattering spectroscopy | Elastic scattering (white light reflectance) | pulsed xenon arc lamp | provides optical geometrical information | 92 | 79 |
Differential path-length spectroscopy | Elastic scattering (white light reflectance) | tungsten-halogen lamp | cell biochemistry, intracellular morphology and microvascular properties such as oxygen saturation and average vessel diameter | 69 | 85 |
Optical Coherence Tomography | scattered light (Fourier domain mode lock swept source-based) OCT | laser-based | Provide provide high-speed three-dimensional OCT pictures | Subjective image required interpretation | Subjective image required interpretation |
Angle-resolved low coherence interferometry (A/LCI) | scattered light to measure the average size of different cell structures | laser-based | delivers direct confirmation of precancerous disease to the physician | 100 | 85 |