DOKKYO MEDICAL UNIVERSITY

Our Resolution
      We know that every athlete wouldn’t be able to be an Olympian and win at the Olympic game. Our physical potentials, intellectual power, and skills differ from each other. The goal and our interests also differ from each other. An organization should not be comprised of homogeneous people, it should be comprised of various kinds of motivated people in various kinds of levels and skills. Therefore, as a team member of a high medical institute, a high clinical performance and high-quality research would be accomplished only by intensively devoting their heart, soul, and time. By polishing our knowledge and skills, we would be useful for patients’ healthcare.
 
A Japanese proverb: The pheasant would not be shot but for its cries
       The pheasant would not be shot but for its cries; avoiding unnecessary talk can prevent disaster from falling on one. It is common in Japanese to be told not to do something special, behave like everybody else, don’t say any more than you can help, just keep a low profile, and be buried among the general public. This is the meaning of the proverb.
     However, my mentors are thinking in a different way for this story. Pheasant is “pheasant” because it cries and flies high, if a pheasant wouldn’t cry, it would be quail. Even if they get shot, they’ll be satisfied because they could live as a pheasant. If you don’t want to get shot, you fly faster, fly higher, and be strong enough to drive back the bullet, and cry.
      Our aim is to establish the best team in which high-level individuals, who own their unique identity and assertiveness without being kept in preconceived idea, get functionally together in our department.  We step forward together aiming for further greater heights without fearing small failures and criticisms.

Clinical features
      The first visiting patients` can check-in from 8 AM to 2 PM every day except Sunday and the third Saturday of the month. On the first visit, the patient is required to be referred from some primary dental office or some medical clinics and hospital with a referral letter. But we accept emergency patients 24 hours a day. For oral malignant and benign tumor, oral cyst, serious odontogenic infection, malocclusion including jaw deformity, cleft lip and palate, temporomandibular joint disease, oral mucosal diseases, jaws and teeth defect needed dental implant treatment, dry mouth including Sjogren's syndrome, sleep apnea, and the general dental diseases (dental caries, periodontitis, missing teeth, etc.) for medically compromised patients, the specialists in each field treat these diseases. In addition, we give oral management for patients with cancers, cardiovascular diseases, orthopedic disease, stroke, etc. during surgery and/or any other treatments.
 

1. Multidisciplinary treatment of oral malignancies: early diagnosis (by CT, MRI, and FDG-PET examination), surgical therapy, radiation therapy, chemotherapy, immunotherapy
2. Treatment of oral and maxillofacial injuries: Prompt diagnosis and treatment for the emergency patients due to traffic injuries etc.
3. Dental implant treatment: Occlusal reconstruction by bone grafting and implant placement for usual tooth loss by dental caries and periodontitis, jaw defect after tumor surgery or trauma.
4. Oral mucosal diseases: Potential oral malignant diseases such as oral lichen planus, oral leukoplakia, stomatitis, oral candidiasis, and oral syphilis. Burning mouth syndrome. Autoimmune diseases such as pemphigus and pemphigoid. Viral disease.
5. Dental treatment of medically compromised patient: Dental treatment for patients with several systemic diseases
6. Oral management: Oral management for patients with cancers, cardiovascular diseases, orthopedic disease, stroke, etc. during surgery and/or any other treatments.
7. Comprehensive and consistent treatment for patients with cleft lip and palate: Hotts plate, cheiloplasty, palatoplasty, speech therapy, orthodontic treatment, orthognathic surgery.
8. Surgical treatment for jaw deformity: Simultaneous movement of the upper and lower jaws for patients with cleft lip and palate, jaw deformity and sleep apnea.
9. Systematic diagnosis and treatment for temporomandibular disorders: Conservative treatment with less invasiveness based on systematic clinical diagnosis and diagnosis by MR examination.
10. Sleep apnea: Treatment of obstructive sleep apnea using an oral appliance, and sometimes by orthognathic surgery.
11. Diagnosis and treatment of Sjogren's syndrome and dry mouth: Diagnosis using evaluation of salivary secretion ability, labial gland biopsy, salivary gland scintigraphy, MR sialography, and measurement of serum autoantibodies.  Drug treatment and oral management will be conducted.

Topics
Oral malignant tumor
      We are trying to make a prompt and reliable diagnosis of the malignant tumor by enhanced CT, MRI, FDG-PET, and biopsy within 2 weeks after the first visit of the patients. Treatment is mainly surgical resection of the tumor according to the latest guidelines. In addition, we are striving to improve the treatment results by combining preoperative administration of S-1 (in order to suppress the tumor growth until surgery) and postoperative chemoradiotherapy including molecular targeted therapy according to the surgical results, histopathological and molecular biological characteristics of the tumor cells. We obtained the five years overall survival rates of 87.5% for Stage 1, 88.8% for Stage 2, 80.9% for Stage 3, and 62.5% for Stage 4. This result might be the world’s highest level.  We are now establishing a genomic diagnosis system for oral cancer by in-house next-generation sequencing (NGS) and microarray analysis. We are also developing oral cancer differentiation induction therapy based on the concept of cancer dormancy therapy. 
 
Dental implants and implants overdentures
      We are conducting dental implant treatment for missing teeth. In addition, we use the implant overdentures to treat cases in which it is difficult to recover masticatory function with conventional dentures, such as cases of tooth defects due to excessive absorption of the mandible and trauma, and cases of mandibular/tooth defects after malignant tumor surgery. We also perform bone grafting for the insufficient jaws or alveolar bone with artificial bone or autologous iliac bone.
 
Oversea medical support
      We have been providing overseas medical support since 2005. So far, we have provided overseas medical support in the Socialist Republic of Vietnam, Mongolia, and Myanmar.
 
Education

School of Medicine:

Graduate School of Medicine:

School of Nursing:

Misato Nursing School Affiliated to Dokkyo Medical University:

Analysis of differentiation-inducing genes in salivary gland cancer
      TSC-22 is a transcriptional regulator containing a leucine zipper-like structure. It has been demonstrated to be upregulated by several stimuli including TGF-beta and EGF. We identified the human gene TSC-22 as an anti-cancer drug (Vesnarinone)-inducible gene in a human salivary gland cancer cell line TYS. It was also demonstrated that suppression of this gene is involved in the development of salivary gland cancer (1,2), and that overexpression significantly enhances the radiosensitivity and anticancer drug sensitivity of salivary gland cancer (3,4,5). TSC-22 transgenic mice were generated and the effect of TSC-22 on the development and carcinogenesis was investigated (6). Most of the Tg-mice showed marked obesity. In histopathological examination of the mice, most of them revealed splenic abnormality, B cell lymphoma was developed. The results indicated the disturbance of normal embryogenesis and lipid metabolism, and further likely induced the oncogenic differentiation of hematopoietic cells.
     We carry various expression vectors, reporter plasmids, and specific antibodies for TSC-22, and we are conducting joint research by donating samples of them at the request of researchers in Japan and overseas. We are currently analyzing the mechanism of action of TSC-22 to further apply our knowledge not only to cancer treatment but also to diagnosis and treatment of various diseases.Kawamata H, Nakashiro K, Uchida D, Hino S, Omotehara F, Yoshida H, Sato M. Induction of TSC-22 by treatment with a new anti-cancer drug, vesnarinone, in a human salivary gland cancer cell. Br J Cancer. 1998; 77(1):71-8.

1. Nakashiro K, Kawamata H, Hino S, Uchida D, Miwa Y, Hamano H, Omotehara F, Yoshida H, Sato M. Down-regulation of TSC-22 (transforming growth factor beta-stimulated clone 22) markedly enhances the growth of a human salivary gland cancer cell line in vitro and in vivo. Cancer Res. 1998 Feb 1; 58(3):549-55.
2. Omotehara F, Uchida D, Hino S, Begum NM, Yoshida H, Sato M, Kawamata H. In vivo enhancement of chemosensitivity of human salivary gland cancer cells by overexpression of TGF-beta stimulated clone-22. Oncol Rep. 2000 Jul-Aug; 7(4):737-40.
3. Hino S, Kawamata H, Omotehara F, Uchida D, Miwa Y, Begum NM, Yoshida H, Sato M, Fujimori T. Cytoplasmic TSC-22 (transforming growth factor-beta-stimulated clone-22) markedly enhances the radiation sensitivity of salivary gland cancer cells. Biochem Biophys Res Commun. 2002;292:957–963.
4. Hino S, Kawamata H, Omotehara F, Uchida D, Miwa Y, Begum NM, Yoshida H, Sato M, Fujimori T. Cytoplasmic TSC-22 (transforming growth factor-beta-stimulated clone-22) markedly enhances the radiation sensitivity of salivary gland cancer cells. Biochem Biophys Res Commun. 2002 Apr 12; 292(4):957-63.
5.  Uchida D., Kawamata H., Omotehara F., Miwa Y., Horiuchi H., Furihata T., Tachibana M., Fujimori T. Overexpression of TSC-22 (transforming growth factor-β-stimulated clone-22) causes marked obesity, splenic abnormality and B cell lymphoma in transgenic mice. Oncotarget. 2016;7:14,310–14,323.

Cancer invasion and metastasis
      We have demonstrated that activation of the extracellular matrix degradation enzymes can promote extravasation and invasive proliferation of cancer cells in the distant organs. It was also shown that there is no correlation between cancer metastasis and the presence of cancer cells in peripheral blood. In our analysis, the major factors that determine metastasis are extravasation of cancer cells in the distant organs, avoiding apoptosis under hypoxia and hyponutrition, angiogenesis, and invasive proliferation.

1. Kawamata H. et al: Cell Growth and Differ., 3: 819-825, 1992.
2. Kawamata H. et al: Int. J. Cancer, 55, 968-973, 1993.
3. Kameyama S., Kawamata H. et al: Carcinogenesis, 14, 1531-1535, 1993.
4.  Kawamata H. et al: Int. J. Cancer, 63: 680-687, 1995.
5. Kawamata H. et al: Int. J. Cancer, 63: 568-575, 1995.
6.  Kawamata H. et al: Int. J. Cancer, 70: 120-127, 1997.
7.  Nakashiro K., Kawamata H. et al: Cancer Res., 58: 549-555, 1998.
8. Kawamata H. et al: Br. J. Cancer, 80: 448-452, 1999.
9. Kawamata H. et al: Int. J. Oncol., 13: 699-704, 1999.
10. Uchida D., Kawamata H. et al: Int. J Cancer, 93: 489-496, 2001.
11. Uchida D., Kawamata H. et al: Br J Cancer, 85: 122-128, 2001.
12.  Furihata T., Sakai T., Kawamata H. et al: Int J Oncol., 19: 903-907, 2001.
13. Sakai T., Furihata T., Kawamata H. et al: Int J Oncol., 21: 547-552, 2002.  

p53 signal pathway gene survey for personalized cancer diagnosis and treatment
      It is well known that there are many abnormalities in p53 and related genes in head and neck cancer, and associations between these abnormalities and anticancer drug sensitivity/radiosensitivity have been reported abundantly. However, the conventional search method only evaluates the static state at the time of biopsy. We have constructed a system for kinetic diagnosis of dysfunction of the entire p53 signaling pathway in cancer cells. Most head and neck cancers have abnormalities in p53 itself or in the p53 signaling pathway due to suppression of the expression of its regulators, and mutations in the p53 gene present in certain cancer cells simply function as tumor suppressor genes. It is a mutation that protects cancer cells from anticancer drugs and radiotherapy (oncogenic mutation).

Identification of origins of oral cancer cells
      Analysis of chronic GVHD-based gingival cancer in patients with leukemia who received peripheral blood stem cell transplantation from their siblings revealed the involvement of sibling-derived cells in recipient’s squamous cell carcinoma. In addition, about 20% of the oral mucosal epithelium of this patient was derived from sibling-derived cells. This indicates that bone marrow-derived cells may repair the epithelium, from which cancer develops (1). In addition, we recently discovered that oral squamous cell carcinoma can be developed not only from the stratified squamous epithelium but also from the salivary glands by microarray survey of oral floor SCC. A group of genes that can easily distinguish the origin of either oral squamous epithelium or salivary gland was identified (2). Since the prognosis of SCC patient differs according to its origin, it can help be helpful in planning treatment for the patients with oral SCC.

1. Hasegawa H, in preparation.
2. Kinouchi M, Izumi S, Nakashiro KI, Haruyama Y, Kobashi G, Uchida D, Hasegawa T, Kawamata H. Determination of the origin of oral squamous cell carcinoma by microarray analysis: Squamous epithelium or minor salivary gland? Int J Cancer. 2018 Nov 15;143(10):2551-2560.  

Integrating the knowledge
      According to the recent development of somatic stem cell research, in the process of repairing the oral mucosal epithelium, (1) epithelial stem cells destined to become oral mucosal epithelium, (2) epithelium destined to become oral tissue Stem cells that can differentiate into both cells and stromal cells, (3) bone marrow stem cells present in the blood, are considered to be involved. In the case of recurrent epithelial damage, (2) or (3) may be mobilized. Epithelium repaired with more undifferentiated stem cells undergoes metaplasia, has high proliferative potential, and genes are unstable, susceptible to mutation, and easily become cancerous. The original characteristics of stem cells are extremely inconvenient for the host when they become cancerous, and they have high infiltration and metastatic potential and become resistant to anticancer drugs and radiation. In the future, we would like to proceed with the development of an essential cancer diagnostic method that considers developing mother cells, which is not affected by the apparent histology of cancer or gene mutation / expression.

Toward treatment
      We think that treatments that induction of cell death before cancer cells emerge from the vasculature in distant organs and proliferate (use of anticancer drugs at the right time, use of molecular targeted therapies, nonspecific immunotherapy, dendritic cells, cancer vaccine, immune check point inhibitors) may lead to suppression of metastasis. Furthermore, we are trying to develop a treatment strategy (cancer dormancy treatment) that induces differentiation of these cancer cells but reduces their proliferative capacity and maintains the state in which cancer cells are present but not proliferating. We are looking forward to sharing these knowledges worldwide in the future.

Japanese Society of Oral and Maxillofacial Surgeons
Japanese Stomatological Society
Japanese Board of Cancer Therapy
Japanese Society of Oral Oncology
Japanese Society of Dentistry for Medically Compromised Patient
Japanese Academy of Maxillofacial Implants
Japanese Society of Oral Implantology
Japanese Society of Oral Medicine
Japanese Society of Pediatric Oral and Maxillofacial Surgery
Japanese Cancer Association
Japan Society of Clinical Oncology
American Association for Cancer Research
European Association for Cranio Maxillo Facial Surgery
Dokkyo Medical Society

Chairman/Professor: Hitoshi Kawamata, D.D.S., Ph.D.
Staff/Associate professor (Lecturer): Takahiro Wakui, D.D.S., Ph.D.
Staff/Associate professor (Lecturer): Atsushi Fujita, D.D.S., Ph.D.
Staff/Associate professor (Lecturer): Sayaka Izumi, D.D.S., Ph.D.
Staff/Assistant professor: Maki Tsubura-Okubo, D.D.S.
Staff/Assistant professor: Masahiro Saito, D.D.S., Ph.D.
Staff/Assistant professor: Yuske Komiyama, D.D.S., Ph.D.
Staff/Assistant professor: Chonji Fukumoto, D.D.S., Ph.D.
Staff/Assistant professor/PhD student: Tomonori Hasegawa, D.D.S.
Staff/Assistant professor: Shuma Yagisawa, D.D.S.
Staff/Assistant professor: Saori Otani, D.D.S., Ph.D.
Staff/Assistant professor: Yosuke Kunitomi, D.D.S., Ph.D.
Staff/Assistant professor: Erika Yaguchi, D.D.S.
Staff/Assistant professor/PhD student: Yuta Sawatani, D.D.S.
Staff/Assistant professor/PhD student: Michiko Shimura, D.D.S.
Staff/Assistant professor: Airi Yamada-Sakamizu, D.D.S.
Staff/Assistant professor: Manabu Zama, D.D.S., Ph.D.
Staff/Senior Resident/PhD student: Ryota Kamimura, D.D.S.
Staff/Senior Resident: Ryo Oshima, D.D.S.
Staff/Senior Resident: Masashi Tani, D.D.S.
Staff/Senior Resident: Amu Fujiwara, D.D.S.
Staff/Senior Resident/PhD student: Masayo Hitomi-Koide, D.D.S.
Staff/Senior Resident/ PhD student: Toshiki Hyodo, D.D.S.
Staff/Senior Resident: Rei Shiraishi, D.D.S.

From C. to C., with C.
This is the motto in our department. The first C denotes the Caries, the second C denotes the Cancer. The last C denotes the Curiosity. We are aiming to establish a department that can comprehensively support the treatment of patients suffering from oral diseases. Furthermore, we act in a manner with curiosity to treat the patients with oral disease and/or to develop new treatment strategies for oral cancer.

Department of Oral and Maxillofacial Surgery

Dokkyo Medical University
Kitakobayashi 880, Mibu, Shimotsuga, Tochigi, 321-0293 Japan