區域癌化觀念最早即是觀察口腔癌所提出的，在惡性腫瘤的發生過程中，因廣泛細胞與致癌物質接觸後，造成多發性的惡性腫瘤新生與再發。區域癌化的研究多針對癌細胞，而非腫瘤微環境。已有許多文獻提到區域癌化可能與間質組織有關，可在細胞或動物實驗發現多發的腫瘤與纖維母細胞變化有關；但一直缺少人體證據。口腔黏膜下纖維化是一與口腔癌有關之間質癌前病變，此病變常伴隨更多的鱗狀上皮細胞異生與口腔癌。在本研究中，第一是比較口腔癌患者中區分純口腔癌組與口腔癌伴隨黏膜下纖維化組，有無口腔黏膜下纖維化是否會在臨床表現與病理分期有影響；第二是比較兩組手術治療後的成果；第三，利用之前初代培養的人類纖維母細胞與台灣口腔癌細胞株進行小鼠腫瘤生成試驗，第四，收集黏膜下纖維化病人唾液，觀察癌化是否會與微生物相有關，第五，觀察比較微生物相的生化功能與細菌互動之差異。觀察短期五年手術治療存活率發現口腔癌伴隨黏膜下纖維化組明顯較為年輕且疾病別存活率較差且容易伴隨第二腫瘤或有局部復發的趨勢。在細胞與小鼠實驗可以發現黏膜下纖維化之纖維母細胞具有促進癌細胞移行、增殖與腫瘤形成的能力。利用高通量的次世代方法定序細菌的16S核醣體V3~V4基因，做細菌種別的區分可以發現有惡轉口腔癌組的細菌多樣性較低、但某些特殊菌種增多，某些多元胺與醛類代謝途徑改變，而細菌互動網路有瓦解情況。因致癌物造成的環境壓力比宿主的控制能力更影響唾液中微生物的組成。離散的菌相分布與中心菌種的降低可在癌化組中發現。藉由機器學習法，我們可藉臨床特徵與特定細菌組合，區分惡轉口腔癌組與未癌化組。
綜合以上，我們有以下建議；一、因口腔黏膜下纖維化族群有好發年輕口腔癌的特性，應盡早轉診黏膜下纖維化病人至專科醫師；二、此類病人雖然張口受限，仍應盡力尋找口腔內第二腫瘤；三、口腔癌病人術後皆需長時間密切追蹤，口腔癌伴隨黏膜下纖維化組較早於五年內有新生、復發與轉移機會，純口腔癌組十年預後只與年齡有關，但部分病人終身持續受口腔癌影響；四、口腔黏膜下纖維化病人是一研究間質細胞造成區域癌化的適當人類模型。希望藉由目前研究結果能提供一些公共衛生的建議，並對口腔癌高危險族群的個人精準醫療，有一些幫助。

The concept of field cancerization is an appropriate explanation for clinical outcomes of oral squamous cell carcinoma (OSCC) because carcinogen-exposed fields develop multifocal malignancies. The rationale of field cancerization emphasizes the evolution of carcinoma cells rather than the tumor microenvironment. Many studies have shown that field cancerization is determined by the stroma; however, human evidence is lacking. Oral submucous fibrosis (OSF) is a premalignant stromal condition that is associated with increased cellular dysplasia and oral cancer formation. First, we compared the clinicopathological characteristics of OSCC patients with and without a history of OSF (OSCC-OSF vs. OSCC only). Second, we compared the surgical prognoses of the two cohorts. Third, patient-derived fibroblasts with a Taiwanese cancer cell line were used to test the tumor formation capabilities in a mouse model. Fourth, we studied the changes in salivary microbiome diversity and composition associated with oral squamous cell carcinoma (OSCC) formation in OSF cases. Lastly, the salivary microbiome of OSF patients and OSF patients with malignant transformation was investigated to determine metabolic function and bacterial interactions. The OSCC-OSF cohort was significantly younger, with poorer 5-year prognosis associated with a higher incidence of second primary head and neck cancer and a trend of more local recurrence. In vivo and in vitro studies showed that OSF fibroblasts can trigger tumor cell migration, proliferation, and formation. High-throughput sequencing of the V3–V4 region in bacterial 16S rRNA of the salivary microbiome revealed OSF and OSCC-OSF with different abundant species, polyamine and formaldehyde biochemical functional shift, and collapsed bacterial networks. Carcinogens result in stochasticity is more important than deterministic effect in shaping the salivary microbiome of patients with OSF. A reduction in the number and abundance of core species suggests dispersion effects on microbiome composition during carcinogenesis in OSF patients.
Taken together, our results suggest the following: (1) because of the nature of the disease, early referral of OSF cases to specialists is essential; (2) in cases where oral cancer is found prior to surgery, more attention may be required to find other oral cancers with limited access; and (3) after surgery, long-term close follow-up for OSCC cases is necessary, especially for second primary and local recurrence in OSCC-OSF and for delayed distant metastasis in the OSCC-only patients. We also demonstrated that OSCC-OSF is a suitable human model to explain stroma as a primary determinant of multifocal epithelial tumors and field cancerization. Through our study, we hope to provide evidence to guide public health recommendations and enhance personalized precision medicine for our compatriots.

Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. 2005. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 43(11):5721-5732.
Acharya A, Chan Y, Kheur S, Kheur M, Gopalakrishnan D, Watt RM, Mattheos N. 2017. Salivary microbiome of an urban indian cohort and patterns linked to subclinical inflammation. Oral Dis. 23(7):926-940.
Adel M, Liao CT, Lee LY, Hsueh C, Lin CY, Fan KH, Wang HM, Ng SH, Lin CH, Tsao CK et al. 2016. Incidence and outcomes of patients with oral cavity squamous cell carcinoma and fourth primary tumors: A long-term follow-up study in a betel quid chewing endemic area. Medicine (Baltimore). 95(12):e2950.
Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ et al. 2017. Nccn guidelines insights: Head and neck cancers, version 2.2017. J Natl Compr Canc Netw. 15(6):761-770.
Ali FM, Aher V, Prasant MC, Bhushan P, Mudhol A, Suryavanshi H. 2013. Oral submucous fibrosis: Comparing clinical grading with duration and frequency of habit among areca nut and its products chewers. Journal of cancer research and therapeutics. 9(3):471-476.
Barach P, Fisher SD, Adams MJ, Burstein GR, Brophy PD, Kuo DZ, Lipshultz SE. 2020. Disruption of healthcare: Will the covid pandemic worsen non-covid outcomes and disease outbreaks? Prog Pediatr Cardiol. 59:101254.
Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. 2004. Tgf-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 303(5659):848-851.
Bornigen D, Ren B, Pickard R, Li J, Ozer E, Hartmann EM, Xiao W, Tickle T, Rider J, Gevers D et al. 2017. Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer. Sci Rep. 7(1):17686.
Braakhuis BJ, Tabor MP, Kummer JA, Leemans CR, Brakenhoff RH. 2003. A genetic explanation of slaughter's concept of field cancerization: Evidence and clinical implications. Cancer Res. 63(8):1727-1730.
Branco ACCC, Yoshikawa FSY, Pietrobon AJ, Sato MN. 2018. Role of histamine in modulating the immune response and inflammation. Mediat Inflamm.
Brands MT, Smeekens EAJ, Takes RP, Kaanders J, Verbeek ALM, Merkx MAW, Geurts SME. 2019. Time patterns of recurrence and second primary tumors in a large cohort of patients treated for oral cavity cancer. Cancer Med. 8(12):5810-5819.
Brennan PA, Arakeri G. 2017. Oral submucous fibrosis—an increasing global healthcare problem. Journal of Oral Pathology & Medicine. 46(6):405-405.
Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, Tan P, Ishimoto T. 2019. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 38(25):4887-4901.
Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, Pontel LB, Rosado IV, Brewer TF, Cordell RL et al. 2017. Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. Nature. 548(7669):549-554.
Cai X, Yao Z, Liu G, Cui L, Li H, Huang J. 2019. Oral submucous fibrosis: A clinicopathological study of 674 cases in china. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 48(4):321-325.
Callahan BJ, McMurdie PJ, Holmes SP. 2017. Exact sequence variants should replace operational taxonomic units in marker-gene data analysis. The ISME journal. 11(12):2639.
Cameron SJ, Huws SA, Hegarty MJ, Smith DP, Mur LA. 2015. The human salivary microbiome exhibits temporal stability in bacterial diversity. FEMS Microbiol Ecol. 91(9):fiv091.
Campisi J, Andersen JK, Kapahi P, Melov S. 2011. Cellular senescence: A link between cancer and age-related degenerative disease? Seminars in cancer biology. 21(6):354-359.
Casero RA, Jr., Murray Stewart T, Pegg AE. 2018. Polyamine metabolism and cancer: Treatments, challenges and opportunities. Nat Rev Cancer. 18(11):681-695.
Caspi R, Billington R, Keseler IM, Kothari A, Krummenacker M, Midford PE, Ong WK, Paley S, Subhraveti P, Karp PD. 2019. The metacyc database of metabolic pathways and enzymes-a 2019 update. Nucleic acids research.
Caussy C, Tripathi A, Humphrey G, Bassirian S, Singh S, Faulkner C, Bettencourt R, Rizo E, Richards L, Xu ZZ et al. 2019. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease. Nat Commun. 10(1):1406.
Chattopadhyay I, Verma M, Panda M. 2019. Role of oral microbiome signatures in diagnosis and prognosis of oral cancer. Technol Cancer Res Treat. 18:1533033819867354.
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W et al. 2011. Human papillomavirus and rising oropharyngeal cancer incidence in the united states. J Clin Oncol. 29(32):4294-4301.
Chaturvedi P, Malik A, Nair D, Nair S, Mishra A, Garg A, Vaishampayan S. 2017. Oral squamous cell carcinoma associated with oral submucous fibrosis have better oncologic outcome than those without. Oral surgery, oral medicine, oral pathology and oral radiology. 124(3):225-230.
Chaturvedi P, Vaishampayan SS, Nair S, Nair D, Agarwal JP, Kane SV, Pawar P, Datta S. 2013. Oral squamous cell carcinoma arising in background of oral submucous fibrosis: A clinicopathologically distinct disease. Head & neck. 35(10):1404-1409.
Chen NH, Djoko KY, Veyrier FJ, McEwan AG. 2016a. Formaldehyde stress responses in bacterial pathogens. Front Microbiol. 7:257.
Chen W-Y, Ng TH, Wu J-H, Chen J-W, Wang H-C. 2017. Microbiome dynamics in a shrimp grow-out pond with possible outbreak of acute hepatopancreatic necrosis disease. Scientific reports. 7(1):9395.
Chen W-Y, Wu J-H, Lin S-C, Chang J-E. 2016b. Bioremediation of polychlorinated-p-dioxins/dibenzofurans contaminated soil using simulated compost-amended landfill reactors under hypoxic conditions. Journal of hazardous materials. 312:159-168.
Cheng YS, Rees T, Wright J. 2014. A review of research on salivary biomarkers for oral cancer detection. Clin Transl Med. 3.
Chinn SB, Myers JN. 2015. Oral cavity carcinoma: Current management, controversies, and future directions. Journal of Clinical Oncology. 33(29):3269-3276.
Chourasia NR, Borle RM, Vastani A. 2015. Concomitant association of oral submucous fibrosis and oral squamous cell carcinoma and incidence of malignant transformation of oral submucous fibrosis in a population of central india: A retrospective study. Journal of maxillofacial and oral surgery. 14(4):902-906.
Chow LQM. 2020. Head and neck cancer. N Engl J Med. 382(1):60-72.
Chuang SC, Scelo G, Tonita JM, Tamaro S, Jonasson JG, Kliewer EV, Hemminki K, Weiderpass E, Pukkala E, Tracey E et al. 2008. Risk of second primary cancer among patients with head and neck cancers: A pooled analysis of 13 cancer registries. Int J Cancer. 123(10):2390-2396.
Chuang SL, Su WW, Chen SL, Yen AM, Wang CP, Fann JC, Chiu SY, Lee YC, Chiu HM, Chang DC et al. 2017. Population-based screening program for reducing oral cancer mortality in 2,334,299 taiwanese cigarette smokers and/or betel quid chewers. Cancer. 123(9):1597-1609.
Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. 2009. Bacterial community variation in human body habitats across space and time. Science. 326(5960):1694.
Curtis M, Kenny HA, Ashcroft B, Mukherjee A, Johnson A, Zhang Y, Helou Y, Batlle R, Liu X, Gutierrez N et al. 2019. Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metab. 29(1):141-155 e149.
Dame ZT, Aziat F, Mandal R, Krishnamurthy R, Bouatra S, Borzouie S, Guo AC, Sajed T, Deng L, Lin H et al. 2015. The human saliva metabolome. Metabolomics. 11(6):1864-1883.
De Wever O, Mareel M. 2003. Role of tissue stroma in cancer cell invasion. The Journal of pathology. 200(4):429-447.
Dey N, Soergel DAW, Repo S, Brenner SE. 2013. Association of gut microbiota with post-operative clinical course in crohn’s disease. BMC Gastroenterology. 13(1):131.
Dotto GP. 2014. Multifocal epithelial tumors and field cancerization: Stroma as a primary determinant. J Clin Invest. 124(4):1446-1453.
Douglas GM, Maffei VJ, Zaneveld J, Yurgel SN, Brown JR, Taylor CM, Huttenhower C, Langille MGI. 2019. Picrust2: An improved and extensible approach for metagenome inference. bioRxiv.672295.
Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A et al. 2016. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 22(12):1428-1438.
Fonknechten N, Perret A, Perchat N, Tricot S, Lechaplais C, Vallenet D, Vergne C, Zaparucha A, Le Paslier D, Weissenbach J et al. 2009. A conserved gene cluster rules anaerobic oxidative degradation of l-ornithine. J Bacteriol. 191(9):3162-3167.
Friedman J, Alm EJ. 2012. Inferring correlation networks from genomic survey data. PLOS Computational Biology. 8(9):e1002687.
Gadbail AR, Chaudhary M, Gawande M, Hande A, Sarode S, Tekade SA, Korde S, Zade P, Bhowate R, Borle R et al. 2017a. Oral squamous cell carcinoma in the background of oral submucous fibrosis is a distinct clinicopathological entity with better prognosis. Journal of Oral Pathology & Medicine. 46(6):448-453.
Gadbail AR, Chaudhary M, Gawande M, Hande A, Sarode S, Tekade SA, Korde S, Zade P, Bhowate R, Borle R et al. 2017b. Oral squamous cell carcinoma in the background of oral submucous fibrosis is a distinct clinicopathological entity with better prognosis. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 46(6):448-453.
Gerner EW, Meyskens FL, Jr. 2004. Polyamines and cancer: Old molecules, new understanding. Nat Rev Cancer. 4(10):781-792.
Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyoty H et al. 2011. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5(1):82-91.
Gluckman JL, Crissman JD. 1983. Survival rates in 548 patients with multiple neoplasms of the upper aerodigestive tract. The Laryngoscope. 93(1):71-74.
Gonzalez-Garcia R, Naval-Gias L, Roman-Romero L, Sastre-Perez J, Rodriguez-Campo FJ. 2009. Local recurrences and second primary tumors from squamous cell carcinoma of the oral cavity: A retrospective analytic study of 500 patients. Head & neck. 31(9):1168-1180.
Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, Sinor PN, Pitkar VK, Murti PR, Irani RR et al. 1980. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of indian villagers. Community Dent Oral Epidemiol. 8(6):283-333.
Hazarey VK, Erlewad DM, Mundhe KA, Ughade SN. 2007. Oral submucous fibrosis: Study of 1000 cases from central india. Journal of Oral Pathology & Medicine. 36(1):12-17.
Hernandez BY, Zhu X, Goodman MT, Gatewood R, Mendiola P, Quinata K, Paulino YC. 2017. Betel nut chewing, oral premalignant lesions, and the oral microbiome. PLOS ONE. 12(2):e0172196.
Holmes I, Harris K, Quince C. 2012. Dirichlet multinomial mixtures: Generative models for microbial metagenomics. PLoS One. 7(2):e30126.
Hong WK, Lippman SM, Itri LM, Karp DD, Lee JS, Byers RM, Schantz SP, Kramer AM, Lotan R, Peters LJ et al. 1990. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. New England Journal of Medicine. 323(12):795-801.
Hopkinson RJ, Schofield CJ. 2018. Deciphering functions of intracellular formaldehyde: Linking cancer and aldehyde metabolism. Biochemistry. 57(6):904-906.
Hosein M, Mohiuddin S, Fatima N. 2015. Association between grading of oral submucous fibrosis with frequency and consumption of areca nut and its derivatives in a wide age group: A multi-centric cross sectional study from karachi, pakistan. Journal of cancer prevention. 20(3):216-222.
Hsiao JR, Chang CC, Lee WT, Huang CC, Ou CY, Tsai ST, Chen KC, Huang JS, Wong TY, Lai YH et al. 2018. The interplay between oral microbiome, lifestyle factors and genetic polymorphisms in the risk of oral squamous cell carcinoma. Carcinogenesis. 39(6):778-787.
Hsue S-S, Wang W-C, Chen C-H, Lin C-C, Chen Y-K, Lin L-M. 2007. Malignant transformation in 1458 patients with potentially malignant oral mucosal disorders: A follow-up study based in a taiwanese hospital. Journal of Oral Pathology & Medicine. 36(1):25-29.
Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, Dotto GP. 2012. Multifocal epithelial tumors and field cancerization from loss of mesenchymal csl signaling. Cell. 149(6):1207-1220.
Hu C, Zhao Y, Wang X, Zhu T. 2021. Intratumoral fibrosis in facilitating renal cancer aggressiveness: Underlying mechanisms and promising targets. Front Cell Dev Biol. 9:651620.
Huang CC, Ou CY, Lee WT, Hsiao JR, Tsai ST, Wang JD. 2015. Life expectancy and expected years of life lost to oral cancer in taiwan: A nation-wide analysis of 22,024 cases followed for 10 years. Oral Oncol. 51(4):349-354.
Huang SY, Chen HM, Liao KH, Ko BS, Hsiao FY. 2020. Economic burden of cancers in taiwan: A direct and indirect cost estimate for 2007-2017. BMJ Open. 10(10):e036341.
Hung MC, Lai WW, Chen HH, Lee JC, Lin YJ, Hsiao JR, Cheng YM, Shan YS, Su WC, Wang JD. 2016. Cost effectiveness of cancer treatment in taiwan. J Formos Med Assoc. 115(8):609-618.
Karpinski TM. 2019. Role of oral microbiota in cancer development. Microorganisms. 7(1).
Kashima H, Noma K, Ohara T, Kato T, Katsura Y, Komoto S, Sato H, Katsube R, Ninomiya T, Tazawa H et al. 2019. Cancer-associated fibroblasts (cafs) promote the lymph node metastasis of esophageal squamous cell carcinoma. Int J Cancer. 144(4):828-840.
Kawasaki M, Tamura T, Harada Y, Fujii N, Doi R, Kodani I. 2020. Clinical features of oral multiple primary carcinomas compared with oral single primary carcinoma. Yonago Acta Med. 63(4):246-254.
Ko HH, Cheng SL, Lee JJ, Chen HM, Wang CW, Cheng SJ, Kok SH. 2016. Factors influencing the incidence and prognosis of second primary tumors in patients with oral squamous cell carcinoma. Head & neck. 38(10):1459-1466.
Ko Y-C, Lai T-Y, Hsu S-C, Wang F-H, Su S-Y, Chen Y-L, Tsai M-L, Wu C-C, Hsiao J-R, Chang J-Y et al. 2020. Index of cancer-associated fibroblasts is superior to the epithelial–mesenchymal transition score in prognosis prediction. Cancers. 12(7):1718.
Krtolica A, Parrinello S, Lockett S, Desprez P-Y, Campisi J. 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proceedings of the National Academy of Sciences. 98(21):12072-12077.
Lee WH, Chen HM, Yang SF, Liang C, Peng CY, Lin FM, Tsai LL, Wu BC, Hsin CH, Chuang CY et al. 2017. Bacterial alterations in salivary microbiota and their association in oral cancer. Sci Rep. 7(1):16540.
Li S, Lee YC, Li Q, Chen CJ, Hsu WL, Lou PJ, Zhu C, Pan J, Shen H, Ma H et al. 2015. Oral lesions, chronic diseases and the risk of head and neck cancer. Oral Oncol. 51(12):1082-1087.
Lian Ie B, Tseng YT, Su CC, Tsai KY. 2013. Progression of precancerous lesions to oral cancer: Results based on the taiwan national health insurance database. Oral Oncol. 49(5):427-430.
Liao C-T, Kang C-J, Chang JT-C, Wang H-M, Ng S-H, Hsueh C, Lee L-Y, Lin CH, Cheng A-J, Chen IH et al. 2007. Survival of second and multiple primary tumors in patients with oral cavity squamous cell carcinoma in the betel quid chewing area. Oral Oncology. 43(8):811-819.
Liao CT, Chang JT, Wang HM, Ng SH, Hsueh C, Lee LY, Lin CH, Chen IH, Huang SF, Cheng AJ et al. 2008. Salvage therapy in relapsed squamous cell carcinoma of the oral cavity: How and when? Cancer. 112(1):94-103.
Liao CT, Wallace CG, Lee LY, Hsueh C, Lin CY, Fan KH, Wang HM, Ng SH, Lin CH, Tsao CK et al. 2014. Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area. Oral oncology.
Liao CT, Wang HM, Ng SH, Yen TC, Lee LY, Hsueh C, Wei FC, Chen IH, Kang CJ, Huang SF et al. 2006. Good tumor control and survivals of squamous cell carcinoma of buccal mucosa treated with radical surgery with or without neck dissection in taiwan. Oral Oncol. 42(8):800-809.
Lim KP, Cirillo N, Hassona Y, Wei W, Thurlow JK, Cheong SC, Pitiyage G, Parkinson EK, Prime SS. 2011. Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. The Journal of pathology. 223(4):459-469.
Liu B, Shen M, Xiong J, Yuan Y, Wu X, Gao X, Xu J, Guo F, Jian X. 2015. Synergistic effects of betel quid chewing, tobacco use (in the form of cigarette smoking), and alcohol consumption on the risk of malignant transformation of oral submucous fibrosis (osf): A case-control study in hunan province, china. Oral surgery, oral medicine, oral pathology and oral radiology. 120(3):337-345.
Liu CH, Chen HJ, Wang PC, Chen HS, Chang YL. 2013. Patterns of recurrence and second primary tumors in oral squamous cell carcinoma treated with surgery alone. Kaohsiung J Med Sci. 29(10):554-559.
Liu G, Dierks EJ, Bell RB, Bui TG, Potter BE. 2012. Post-therapeutic surveillance schedule for oral cancer: Is there agreement? Oral and Maxillofacial Surgery. 16(4):327-340.
Impact of coronavirus on personal health,economic and food security, and medicaid. 2020. [accessed]. https://www.kff.org/report-section/kff-health-tracking-poll-may-2020-health-and-economic-impacts/.
Lopez-Novoa JM, Nieto MA. 2009. Inflammation and emt: An alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 1(6-7):303-314.
Lozupone CA, Hamady M, Kelley ST, Knight R. 2007. Quantitative and qualitative beta diversity measures lead to different insights into factors that structure microbial communities. Appl Environ Microbiol. 73(5):1576-1585.
Mager DL, Haffajee AD, Devlin PM, Norris CM, Posner MR, Goodson JM. 2005. The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. Journal of Translational Medicine. 3(1):27.
Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, Upile T, Kalavrezos N, Violette SM, Weinreb PH et al. 2011. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol. 223(4):470-481.
Meuric V, Le Gall-David S, Boyer E, Acuña-Amador L, Martin B, Fong SB, Barloy-Hubler F, Bonnaure-Mallet M. 2017. Signature of microbial dysbiosis in periodontitis. Applied and Environmental Microbiology. 83(14):e00462-00417.
Meyer MS, Joshipura K, Giovannucci E, Michaud DS. 2008. A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer Causes & Control. 19(9):895-907.
Mochizuki Y, Harada H, Ikuta M, Shimamoto H, Tomioka H, Tanaka K, Hirai H, Omura K. 2015. Clinical characteristics of multiple primary carcinomas of the oral cavity. Oral Oncol. 51(2):182-189.
Mukherjee PK, Wang H, Retuerto M, Zhang H, Burkey B, Ghannoum MA, Eng C. 2017. Bacteriome and mycobiome associations in oral tongue cancer. Oncotarget. 8(57):97273-97289.
Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. 1985. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community dentistry and oral epidemiology. 13(6):340-341.
Navazesh M. 1993. Methods for collecting saliva. Ann N Y Acad Sci. 694:72-77.
Nigam NK, Aravinda K, Dhillon M, Gupta S, Reddy S, Srinivas Raju M. 2014. Prevalence of oral submucous fibrosis among habitual gutkha and areca nut chewers in moradabad district. Journal of oral biology and craniofacial research. 4(1):8-13.
Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. 2010. Dietary vitamin k intake in relation to cancer incidence and mortality: Results from the heidelberg cohort of the european prospective investigation into cancer and nutrition (epic-heidelberg). The American Journal of Clinical Nutrition. 91(5):1348-1358.
Ning D, Deng Y, Tiedje JM, Zhou J. 2019. A general framework for quantitatively assessing ecological stochasticity. Proc Natl Acad Sci U S A. 116(34):16892-16898.
Nishio T, Yoshikawa Y, Shew CY, Umezawa N, Higuchi T, Yoshikawa K. 2019. Specific effects of antitumor active norspermidine on the structure and function of DNA. Sci Rep. 9(1):14971.
Noens EE, Kaczmarek MB, Zygo M, Lolkema JS. 2015. Arcd1 and arcd2 arginine/ornithine exchangers encoded in the arginine deiminase pathway gene cluster of lactococcus lactis. J Bacteriol. 197(22):3545-3553.
Nowotarski SL, Woster PM, Casero RA, Jr. 2013. Polyamines and cancer: Implications for chemotherapy and chemoprevention. Expert Rev Mol Med. 15:e3.
Organization WH. 1984. Control of oral cancer in developing countries. Bull World Hlth Org. 62:817-830.
Paget S. 1889. The distribution of secondary growths in cancer of the breast. 1889. Cancer metastasis reviews. 8(2):98-101.
Pati A, Gronow S, Lu MG, Lapidus A, Nolan M, Lucas S, Hammon N, Deshpande S, Cheng JF, Tapia R et al. 2011. Non-contiguous finished genome sequence of the opportunistic oral pathogen prevotella multisaccharivorax type strain (pppa20(t)). Stand Genomic Sci. 5(1):41-49.
Patrucco MS, Aramendi MV. 2016. Prognostic impact of second primary tumors in head and neck cancer. Eur Arch Otorhinolaryngol. 273(7):1871-1877.
Pedregosa F, Varoquaux G, Gramfort A, Michel V, Thirion B, Grisel O, Blondel M, Prettenhofer P, Weiss R, Dubourg V. 2011. Scikit-learn: Machine learning in python. Journal of machine learning research. 12(Oct):2825-2830.
Perera M, Al-Hebshi NN, Perera I, Ipe D, Ulett GC, Speicher DJ, Chen T, Johnson NW. 2018. Inflammatory bacteriome and oral squamous cell carcinoma. J Dent Res. 97(6):725-732.
Petersen PE, Bourgeois D, Ogawa H, Estupinan-Day S, Ndiaye C. 2005. The global burden of oral diseases and risks to oral health. Bull World Health Organ. 83(9):661-669.
Piersma B, Hayward MK, Weaver VM. 2020. Fibrosis and cancer: A strained relationship. Biochim Biophys Acta Rev Cancer. 1873(2):188356.
Pindborg JJ. 1972. Is submucous fibrosis a precancerous condition in the oral cavity? Int Dent J. 22(4):474-480.
Prabhu RV, Prabhu V, Chatra L, Shenai P, Suvarna N, Dandekeri S. 2014. Areca nut and its role in oral submucous fibrosis. Journal of clinical and experimental dentistry. 6(5):e569-575.
Proctor LM, Creasy HH, Fettweis JM, Lloyd-Price J, Mahurkar A, Zhou W, Buck GA, Snyder MP, Strauss JF, Weinstock GM et al. 2019. The integrative human microbiome project. Nature. 569(7758):641-648.
Rajendran R. 1994. Oral submucous fibrosis: Etiology, pathogenesis, and future research. Bull World Health Organ. 72(6):985-996.
Rennemo E, Zatterstrom U, Boysen M. 2008. Impact of second primary tumors on survival in head and neck cancer: An analysis of 2,063 cases. Laryngoscope. 118(8):1350-1356.
Roje S. 2006. S-adenosyl-l-methionine: Beyond the universal methyl group donor. Phytochemistry. 67(15):1686-1698.
Sarode SC, Sarode GS. 2013. Better grade of tumor differentiation of oral squamous cell carcinoma arising in background of oral submucous fibrosis. Medical hypotheses. 81(4):540-543.
Schirmer CM, Ringer AJ, Arthur AS, Binning MJ, Fox WC, James RF, Levitt MR, Tawk RG, Veznedaroglu E, Walker M et al. 2020. Delayed presentation of acute ischemic strokes during the covid-19 crisis. J Neurointerv Surg. 12(7):639-642.
Schwam ZG, Judson BL. 2016. Improved prognosis for patients with oral cavity squamous cell carcinoma: Analysis of the national cancer database 1998-2006. Oral Oncol. 52:45-51.
Sharma M, Radhakrishnan R. 2017. Limited mouth opening in oral submucous fibrosis: Reasons, ramifications, and remedies. Journal of Oral Pathology & Medicine. 46(6):424-430.
Siegel RL, Miller KD, Jemal A. 2015. Cancer statistics, 2015. CA Cancer J Clin. 65(1):5-29.
Siegel RL, Miller KD, Jemal A. 2018. Cancer statistics, 2018. CA Cancer J Clin. 68(1):7-30.
Singh G, Rana AS, Kumar A, Prajapati A, Kumar S, Singh P. 2017. Nodal involvement in oral squamous cell carcinoma (scc) patients with and without oral sub mucous fibrosis (osmf): A comparative study. Journal of oral biology and craniofacial research. 7(3):171-177.
Siriwardena B, Jayawardena K, Senarath NH, Tilakaratne WM. 2018. An evaluation of clinical and histopathological aspects of patients with oral submucous fibrosis in the background of oral squamous cell carcinoma. Biomed Res Int. 2018:4154165.
Slaughter DP, Southwick HW, Smejkal W. 1953. “Field cancerization” in oral stratified squamous epithelium. Clinical implications of multicentric origin. Cancer. 6(5):963-968.
Stahringer SS, Clemente JC, Corley RP, Hewitt J, Knights D, Walters WA, Knight R, Krauter KS. 2012. Nurture trumps nature in a longitudinal survey of salivary bacterial communities in twins from early adolescence to early adulthood. Genome Res. 22(11):2146-2152.
Su WW, Chuang SL, Yen AM, Chen SL, Fann JC, Chiu SY, Chiu HM, Su CW, Hsu CY, Chen MK et al. 2019. Risk for a second primary hypopharyngeal and esophageal cancer after an initial primary oral cancer. Oral Dis. 25(4):1067-1075.
Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, van der Wal JE, Snow GB, Leemans CR, Braakhuis BJM. 2002. Multiple head and neck tumors frequently originate from a single preneoplastic lesion. The American Journal of Pathology. 161(3):1051-1060.
Takeshita T, Kageyama S, Furuta M, Tsuboi H, Takeuchi K, Shibata Y, Shimazaki Y, Akifusa S, Ninomiya T, Kiyohara Y et al. 2016. Bacterial diversity in saliva and oral health-related conditions: The hisayama study. Sci Rep. 6:22164.
Tang H, Wu Z, Zhang J, Su B. 2013. Salivary lncrna as a potential marker for oral squamous cell carcinoma diagnosis. Mol Med Rep. 7.
The Human Microbiome Project C, Huttenhower C, Gevers D, Knight R, Abubucker S, Badger JH, Chinwalla AT, Creasy HH, Earl AM, FitzGerald MG et al. 2012. Structure, function and diversity of the healthy human microbiome. Nature. 486:207.
Toratani S, Ogawa I, Sasahara H, Yoshioka Y, Kanda T, Tani R, Okamoto T. 2019. Pathological factors involved in local failure in squamous cell carcinoma of the oral cavity: Retrospective study and proposal of a new clinical classification. International Journal of Oral and Maxillofacial Surgery. 48(2):143-151.
Upp JR, Jr., Saydjari R, Townsend CM, Jr., Singh P, Barranco SC, Thompson JC. 1988. Polyamine levels and gastrin receptors in colon cancers. Ann Surg. 207(6):662-669.
van 't Hof W, Veerman EC, Nieuw Amerongen AV, Ligtenberg AJ. 2014. Antimicrobial defense systems in saliva. Monogr Oral Sci. 24:40-51.
Vinjamuri S, Dontaraju VS, Munirathinam G. 2020. Chapter 29 - prostate cancer and applications of vitamin k. In: Patel VB, editor. Molecular nutrition. Academic Press. p. 613-629.
Wade WG. 2013. The oral microbiome in health and disease. Pharmacological Research. 69(1):137-143.
Warren S, Gates O. 1932. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer. 16:1358-1414.
Willis JR, Gonzalez-Torres P, Pittis AA, Bejarano LA, Cozzuto L, Andreu-Somavilla N, Alloza-Trabado M, Valentin A, Ksiezopolska E, Company C et al. 2018. Citizen science charts two major "stomatotypes" in the oral microbiome of adolescents and reveals links with habits and drinking water composition. Microbiome. 6(1):218.
Xu S, Hao N, Xu L, Liu ZX, Yan M, Li Y, Ouyang PK. 2015. Series fermentation production of ornithine and succinic acid from cane molasses by corynebacterium glutamicum. Biochem Eng J. 99:177-182.
Yamauchi M, Barker TH, Gibbons DL, Kurie JM. 2018. The fibrotic tumor stroma. J Clin Invest. 128(1):16-25.
Yang PY, Chen YT, Wang YH, Su NY, Yu HC, Chang YC. 2017. Malignant transformation of oral submucous fibrosis in taiwan: A nationwide population-based retrospective cohort study. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.n/a-n/a.
Yang S-F, Wang Y-H, Su N-Y, Yu H-C, Wei C-Y, Yu C-H, Chang Y-C. 2018a. Changes in prevalence of precancerous oral submucous fibrosis from 1996 to 2013 in taiwan: A nationwide population-based retrospective study. J Formos Med Assoc. 117(2):147-152.
Yang SF, Huang HD, Fan WL, Jong YJ, Chen MK, Huang CN, Chuang CY, Kuo YL, Chung WH, Su SC. 2018b. Compositional and functional variations of oral microbiota associated with the mutational changes in oral cancer. Oral Oncol. 77:1-8.
Zaneveld JR, McMinds R, Vega Thurber R. 2017. Stress and stability: Applying the anna karenina principle to animal microbiomes. Nature Microbiology. 2(9):17121.
Zarco MF, Vess TJ, Ginsburg GS. 2012. The oral microbiome in health and disease and the potential impact on personalized dental medicine. Oral Dis. 18(2):109-120.
Zaura E, Brandt BW, Teixeira de Mattos MJ, Buijs MJ, Caspers MP, Rashid MU, Weintraub A, Nord CE, Savell A, Hu Y et al. 2015. Same exposure but two radically different responses to antibiotics: Resilience of the salivary microbiome versus long-term microbial shifts in feces. mBio. 6(6):e01693-01615.
Zhao H, Chu M, Huang Z, Yang X, Ran S, Hu B, Zhang C, Liang J. 2017. Variations in oral microbiota associated with oral cancer. Scientific Reports. 7(1):11773.
Zhong X, Lu Q, Zhang Q, He Y, Wei W, Wang Y. 2020. Oral microbiota alteration associated with oral cancer and areca chewing. Oral diseases.