Department of
Cardiothoracic Surgery
Outline and Research Objectives
Our department specializes in all areas of cardiothoracic surgery including congenital andacquired cardiac diseases, thoracic and abdominal aortic diseases, and benign and malignant
diseases of respiratory and mediastinal organs, except for diseases of the esophagus andmammary glands. The Department of Cardiothoracic Surgery, University of Tokyo, wasestablished in December 15, 1964 as the first department of this field in the Japanesenational universities. Since then it has played an internationally leading role and contributed to development of the field. Professors and Chairs in the history of the department
are as follows; Seiji Kimoto (1964.12.15 ~ 1968.3.31), Masahiro Saigusa (1968.4.1 ~1981.3.31), Ken-ichi Asano (1981.4.1 ~ 1986.3.31), Akira Furuse (1986.4.1 ~ 1997.3.31) and
Shinichi Takamoto (1997.6.1 ~). The cardiothoracic department of the University of Tokyo
has created highly active research programs in the every field of cardiothoracic surgery.
Recently, most of the basic research activities are focused in the fields of brain and spinal
cord protection during aortic surgery, homo- and xeno-transplantation of the heart, lung,heart valves and trachea, and surgical oncology of the pulmonary and thymic neoplasms.
Although, there are many other active research projects such as stent-graft repair for thoracic aortic aneurysm, minimally invasive cardiac surgery, and intraoperative real-time 3-D
echocardiography.

Faculties and Students
Professor and Chair Shinichi Takamoto,M.D. (1997-)
Associate Professors Yutaka Kotsuka, M.D
Jun Nakajima, M.D.
Lecturer
Arata Murakami, M.D. andToshiya Ohtsuka, M.D.
Associate .................................8
Graduate Students ................10
Research Students...................1

Past Research and Major Accomplishments
Dr. Takamoto invented a new method of brain
protection during surgery of a distal arch aneurysm
under deep hypothermia (Fig 1). The new method is akind of retrograde cerebral perfusion, which simplify
the retrograde perfusion system for patients of distal
aortic arch aneurysmon. This new method has been
accepted as a standard procedure of a distal arch
replacement in all over the world. The method has
been applied to many patients, and it was clarified
that the method provides a prolongation of safety limits of circulatory arrest and a beneficial effect in prevention of brain embolism.
Allograft tissue has sevral advantages in that antiinfection, softness, and less compliance mismatching.
Cell viability of the tissue can be maintained for morethan hundred years if properly preserved under theliquid nitrogen. We started basic study on homografts

Fig 1

Fig 2

tissue transplantation including the cardiac valve,aorta and trachea 8 years ago. We founded the
Universty of Tokyo Tissue Bank (UTTB) in 1999,
where human cardiac valves, vessels and tracheas

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obtained from non-brain dead donors are cryopreserved. Cardiac valves are used for the patients ofinfective endocarditis, congenital heart disease.
Vessels are used for artificial graft infection, livertransplant recipients. The number of donor and usageof these allogaft tissus are increasing every year, andmore and more patients are being saved with these
allograft tissues (Fig 2).
As for clinical activities, surgical cases are remarkably increasing as shown in the table below.
Table 1: Patients who underwent surgery in the department
Cardiovascular
General Thoracic
Total

1997
152
178
330

1998
157
202
359

1999
179
170
349

2000
225
197
422

2001
272
185
457

Current Research
Thirteen staff members including professors andlecturers all participate not only in surgeries but alsopatient care on both in-patient and out-patient bases.
They are all engaged in research activities for clinicaland experimental subjects. As the subjects of cardiothoracic surgical fields are so close one another, we do
not have sectioned research groups within our department. Instead, we make a project team for eachresearch subject with most appropriate staff members
and residents. Every associate takes part in at least
one to several project teams. Main subjects of current
research includes brain and spine protection during
aortic surgery, homo- and xeno-transplantation of theheart, lung, heart valves and and trachea, surgicaloncology of the pulmonary and thymic neoplasms,
stent-graft repair for thoracic aortic aneurysm, minimally invasive cardiac surgery, and intraoperative 3-D
echocardiography.
Spinal cord protection: Paraplegia remains one of
the most serious complications after thoracoabdominal aortic aneurysm repair. In order to prevent paraplegia, it is important to identify and preserve criticalsegmental arteries. We developed new method to
identify critical segmental artery. The ultrasonographic evaluation of the hemodynamics of intercostal
arteries was the key to identify critical segmental
artery (Fig 3).
Cryopreserved allotransplantation: Cryopreserved
allogeneic heart valves and vessels have come to be
widely utilized in cardiothoracic surgery because of
their excellent durability. We have studied the allogenicity of the cryopreserved tissues using cell cultures of the airway epithelium, vascular endothelium,and fibroblasts. We have investigated whether cryopreserved tracheal allotransplantation is applicable.
Experimental cryopreserved tracheal allotransplanta-

224

tion was performed in primates, which have a closer
anatomical and immunological relation with humans
than other animals, to confirm the possible clinicalfeasibility of cryopreserved tracheal allotransplantation. Immunogenicity was attenuated by cryopreservation, and cryopreserved tracheal allografts wereincorporated in all animals (Fig 4).
Stent-graft repair: We developed ultrathin-wallvascular grafts with a wall thickness of 42 to 137μm
for endovascular surgery. We studied the physicalproperties of the ultrathin-wall grafts in in vitro
experiments. We conclude that the newly developed
ultrathin-wall grafts are suitable for endovascular surgery (Table 2).
After animal experiments, we applied the grafts toclinical patients with good results. We also developed
auto-swelling vascular grafts, using ultrathin-wall
Dacron vascular grafts and superabsorbent polymer.
These grafts were designed to prevent endoleak following stent-graft repair of aortic aneurysm. Stentgrafts covered with auto-swelling grafts are expected
to have beneficial effects in preventing endoleak.
Minimally invasive cardiac surgery: We have beenusing minimally invasive techniques in various procedures of thoracic and cardiac surgery. We have
employed video-assisted thoracoscopic surgery (VATS)
for pulmonary or mediastinal surgery since 1992. We
have made retrospective studies on feasibility and surgical outcome of VATS for diagnosis and treatment oflung neoplasms. We have concluded that VATS for
diagnosing pulmonary indeterminate nodules and

fig3

fig4

Table 2
Wall thickness (µm)

137

117

95

85

75

64

50

42

Transverse Microscopic
Porosity (µm)

0

0

0

0

0

11.3±13.6

57.4±25.0

75.9±18.8

Longitudinal Microscopic
Porosity (µm)

0

0

0

0

0

36.9±7.8

39.0±7.9

132.3± 7.8

Planimetric Porosity
(µm2)

0

0

0

0

0

416±494

2,238±1193>10,000

Longitudinal Tensile
Strength (Kg)22.5±2.0

19.4±1.2

15.3±0.8

14.1±1.8

13.1±0.9

9.5±0.9

7.4±0.5–

Water Permeability(ml/min/cm2)

330±17220±20250±36180±17380±531,700±361

2,960±443

3,840±668

fig6
fig5

VATS for pulmonary metastasectomy are justified as astandard therapeutics. Off-pump coronary artery
bypass is achieved without hemodynamic assistanceby cardiopulmonary bypass, and it has been applied
to increasing number of patients with multi-vessel
ischemic heart disease. A single bypass from theinternal mammary artery (IMA) to the left anterior
descending coronary artery has been accomplished via
a mini-thoracotomy approach. Valvular disease or atrial septal defect have been repaired via a limited sternotomy using a special retractor and port-accessible
heart-lung machine. Video-endoscopy has been positively used for minimally invasive approach.
Thoracoscopy has been used for mobilization of ITA
graft (Fig 5), and cardioscopy has been used in valvular repair, correction of intra-cardiac anomaly, andleft-atrial cryo-ablation.
Real-time 3-D echocardiography: We have developed real-time three-dimensional echocardiography(RT3DE) and applied it to monitoring heart operations, especially ASD closure, as a means of assistingtreatment (Fig 6). In the animal experiment, ASD was
successfully closed by RT3DE monitoring, and examination of the excised heart showed that all sutures
were located, and the reliability of the images
obtained by RT3DE was confirmed.
Surgical oncology of the thymic neoplasms: Toclassify the thymic epithelial neoplasms, the maturation stage of T-lineage lymphoid cells infiltrating
thymic neoplasms (TIL) was examined by flow-

cytometry to associate it with the degree of tumor
malignancy. CD4+CD8+ or CD10+ T-lineage cells werethe most reliable markers of the benignancy of thymic
epithelial tumors. CD4 / CD8 single positive cells or
CD20-positive cells were characteristic in thymic carcinoma. Flow-cytometry on the maturity of lymphoidcells infiltrating thymic epithelial tumors was feasiblefor determining their degree of malignancy. Recently
we have investigated T-cell receptor (TCR) gene rearrnagement of the TIL. We have observed the appearance of clonal bands in TCR-beta and gamma, suggesting that partial gene rearrangement occurred in the
TIL.

Future Prospects
Cardiac Transplantation is established treatment in
the world. However, this treatment has not been welldeveloped in Japan due to domestic reasons. We are
now preparing clinical cardiac transplantation. We aregoing to develop basic and clinical research on cardiac
transplantation as well as clinical application.

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Research Grants
1. Grant-in Aid for Scientific Research from theJapanese Ministry of Education, Science, Sports andCulture (A)(1): Studies on management of hearttransplant recipients and maintenance of donororgans. 1998-2000
2. Grant-in-Aid for Publication of Scientific Research
Results: Japan Adult Cardiovascular Surgery
Database. 2002
3. Grant-in-Aid for University and Society
Collaboration: Establishment of Tissue Banking
System on the basis of regional linkage. 2000-2002
4. Grant-in Aid for Scientific Research from theJapanese Ministry of Education, Science, Sports andCulture (B)(2): Basic and clinical study on percutaneous endovascular surgery with ultrathin-wall vascular grafts. 1997-1998
5. Grant-in Aid for Scientific Research from theJapanese Ministry of Education, Science, Sports andCulture (B)(2): Development of auto-swelling vasculargrafts using super-absorbent polymer. 1999-2001

Select Publications
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9.

Imanaka, K., Takamoto S. Furuse A. Mitral regurgitation late after Manouguian’s anulus enlargement
and aortic valve replacement. J Thorac Cardiovasc
Surg 115, 727-9, 1998.
Ono, M, Takamoto S, Ohtsuka T. Right ventricularrupture in a minimally invasive direct coronary
artery bypass grafting. Eur Journal Cardiothorac Surg
14, 536-537, 1998.
Imanaka K. Shimizu S. Matsumoto J. Hashizume K.
Tsuchiya K. Takemura T. Unilateral absence of pulmonary artery and ventricular defect in an infant.
Ann Thorac Surg 66, 251-2, 1998.
Kawauchi M, Nakajima J, Takeda M, Oka T,
Takamoto S. Aortic valves are antigenic but less sothan myocardium. J Thorac Cardiovasc Surg 116,
532, 1998.
Miyaji K, Sugiura S, Omata S, Kaneko Y, Ohtsuka T,
Takamoto S. Myocardial tactile stiffness: A variableof regional myocardial function. J Am Coll Cardiol
31, 1165-1173, 1998.
Kubota H, Takamoto S. Takeshita M. Miyaji K.
Kotsuka Y. Furuse A. Atrial ablation with an IRK-151
infrared coagulator. Ann Thorac Surg 66, 95-100,
1998.
Ohtsuka T, Takamoto S, Endoh M, Ono M, Minami
M. Ultrafast computed tomography for minimallyinvasive coronary artery bypass grafting. J Thorac
Cardiovasc Surg 116, 173-4, 1998.
Ohtsuka T, Endoh M, Takamoto S. Minimally invasive left anterior descending coronary artery bypass
with right gastroepiploic artery graft. J Thorac
Cardiovasc Surg 116, 528-9, 1998.
Ohtsuka T. How high should mammary artery be
harvested for the minimally invasive approach? Ann
Thorac Surg 66, 985-6, 1998.

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10. Kotsuka Y, Tanaka O, Takamoto S, Furuse A.
Intravalvular implantation technique for aortic valve
replacement in aortitis syndrome. Ann Thorac Surg
67, 89-92, 1999.
11. Imanaka K, Takamoto S, Murakami A, Kaneko Y.
Minimally invasive extracardiac conduit replacement
via a left anterior small thoracotomy. J Thorac
Cardiovasc Surg 118, 1124-5, 1999.
12. Imanaka, K, Takamoto S, Kaneko Y, Murakami A,
Shibuya K. Extracardiac conduit replacement withautologous tissue only, via a left anterior small thoracotomy. Thorac Cardiovasc. Surg 47, 251-2, 1999.
13. Imanaka, K, Takamoto S, Murakami A, Kaneko Y.
Right ventricular thrombosis early after bidirectional
Glenn shunt. Ann Thorac Surg 68, 563-5, 1999.
14. Ohtsuka T, Imanaka K, Endoh M, Kohno T,
Nakajima J, Kotsuka Y, Takamoto S. Hemodynamic
effects of carbon dioxide insufflation under singlelung ventilation during thoracoscopy. Ann Thorac
Surg 68, 29-33, 1999.
15. Nakajima J, Poindexter NJ, Hillemeyer PB, Trulock
EP, Cooper JD, Patterson GA, Mohanakumar T,
Sundaresan RS. Cytotoxic T lymphocytes directedagainst donor HLA class I antigens on airway epithelial cells are present in bronchoalveolar lavage fluid
from lung transplant recipients during acute rejection. J Thorac Cardiovasc Surg 117, 565-71, 1999.
16. Nakajima J., Furuse A, Kohno T, Ohtsuka T,
Matsumoto J, Oka T. Transthoracoscopic needle
biopsy for indeterminate lung nodules. SurgicalEndoscopy 13, 386-9, 1999.
17. Tanaka K, Takamoto S, Ohtsuka T, Kotsuka Y.
Advaseal for acute aortic dissection: experimental
study. Eur J Cardio-thorac Surg 15, 114-115, 1999.
18. Tanaka K, Takamoto S, Ohtsuka T, Kotsuka Y,
Kawauchi M. Application of Advaseal for acute aortic
dissection: experimental study. Ann Thorac Surg 68,
1308-1313, 1999.
19. Murakawa T, Nakajima J, Ono M, Murakami A,
Suematsu Y, Takamoto S.: Allogenicity of cryopreserved human fibroblasts: cryopreservation does not
downregulate the allogenicity of fibroblasts making
up the matrices of allografts. J Thorac Cardiovasc
Surg 120, 712-9, 2000.
20. Murakawa T, Nakajima J, Kohno T, Tanaka M,
Matsumoto J, Takeuchi E, Takamoto S. Results fromsurgical treatment for thymoma: 43 years of experience. Jpn J Thorac Cardiovasc Surg 48, 89-95, 2000.
21. Kubota H, Furuse A, Kotsuka Y, Ninomiya M, Miyaji
K, Endo M, & Takamoto S: Cardiac function evaluated by transesophageal echocardiography during cardiopulmonary bypass. Jpn J Thorac Cardiovasc Surg48, 261-266, 2000.
22. Kubota H, Takamoto S, Kotsuka Y, & Furuse A:
Successful treatment of massive pulmonary tumor
embolism from renal cell carcinoma. Ann Thorac
Surg 69, 972-3, 2000.
23. Kubota H, Takamoto S, Takeshita M, Miyaji K,
Kotsuka Y, & Furuse A: Atrial ablation using an lRK-

151 infrared coagulator in canine model. J Cardiovasc
Surg 4, 835-47, 2000.
24. Nakajima J, Takamoto S, Oka T, Tanaka M,
Takeuchi E, Murakawa T : Flow cytometric analysis
of lymphoid cells in thymic epithelial neoplasms. Eur
J Cardiothorac Surg 18, 287-92, 2000.
25. Nakajima J, Takamoto S, Tanaka M, Takeuchi E,
Murakawa T : Thoracoscopic resection of the pulmonary aspergilloma - Report of two cases. Chest
118, 1490-2, 2000.
26. Nakajima J, Takamato S, Kohno T, Ohtsuka T: Costsof videothoracoscopic surgery versus open resection
for patients with of lung carcinoma. Cancer 89, 24972501, 2000.
27. Kotsuka Y, Ezure M, Kawauchi M, Takamoto S:
Swinging motion of intimal flap through the aortic
valve in acute aortic dissection. J Cardiovasc Surg 41,
395-397, 2000.
28. Ono M., Takamoto S., Kawauchi M., Egami M.,
Kotsuka Y.: Aortobronchial fistula late after transverse arch replacement. Ann Thorac Surg 70, 964-6,
2000.
29. Suematsu Y. Ohtsuka T. Miyaji K. Murakami A.
Miyairi T. Eyileten Z. Kotsuka Y. Takamoto S. Rightheart mini-pump bypass for coronary artery bypass
grafting: experimental study. Eur J Cardio-Thoracic
Surg 18, 276-81, 2000.
30. Murakawa T, Nakajima J, Tanaka M, Karita M,
Takamoto S.: Primary low-grade B-cell lymphoma in
mucosa-associated lymphoid tissue of the lung. Jpn J
Thorac Cardiovasc Surg 49, 621-4, 2001.
31. Ohtsuka T, Suematsu Y, Kubota H, Takamoto S,
Makuuchi M. Salvage of right gastroepiploic artery
graft before pancreatoduodenectomy. J Thorac
Cardiothorac Surg 121, 1013-4, 2001.
32. Ohtsuka T, Kubota H, Motomura N, Takamoto S.
Thoracoscopy for minimally invasive axillo-coronary
artery bypass. Eur J Cardiothorac Surg 20, 856-7,
2001.
33. Ohtsuka T, Nakajima J, Kotsuka Y, Takamoto S.
Hemodynamic responses to intra-pleural insufflation
with hemipulmonary collapse. Surg Endosc 15, 132730, 2001.
34. Ohtsuka T, Takamoto S, Ono M, Motomura N.
Aortic root replacement and coronary Interposition
using a cryopreserved allograft and its branch. Eur J
Cardiothorac Surg 20, 631-2, 2001.
35. Mikio Ninomiya, Jun Nakajima, Makoto Tanaka,
Eriho Takeuchi, Tomohiro Murakawa, Takeshi
Fukami, Shinichi Takamoto: Effects of lung metastasectomy on respiratory function. Jpn J Thorac
Cardiovasc Surg 49, 17-20, 2001.
36. Mikio Ninomiya, Shinichi Takamoto, Yutaka
Kotsuka, Takeshi Miyairi, Munemoto Endo: Stentgraft implantation through partial sternotomy. J
Thorac Cardiovasc Surg 121: 992-993, 2001.
37. Mikio Ninomiya, Shinichi Takamoto, Yutaka
Kotsuka, Toshiya Ohtsuka: Indication and perioperative management for cardiac surgery in patients withliver chirrhosis: Our experience with 3 patients. Jpn J
Thorac Cardiovasc Surg 49, 391-394, 2001.
39. Mikio Ninomiya, Haruo Makuuchi, Toshiya
Ohtsuka, Shinichi Takamoto: Ischemic heart diseaseassociated with protein C deficiency. Eur J
Cardiothorac Surg 20, 883-885, 2001.
40. Mikio Ninomiya, Shinichi Takamoto, Yutaka
Kotsuka, Takeshi Miyairi, Tetsuro Morota, Hiroshi
Kubota: Midterm results after aortic valve-sparing
operation. Jpn J Thorac Cardiovasc Surgery 49, 706710, 2001.
41. Ono M., Takamoto S., Miyairi T., Kubota H.: An
extended repair of thoracic aorta through left thoracotomy after aortic root replacement. Ann Vasc Surg
15, 488-90, 2001.
42. Ono M., Wolf R.K.: Heart injury and endocarditis
caused by a needle migrated from the left arm. Eur J
Cardiothorac Surg 20, 1073-4, 2001.
43. Ueno K, Takamoto S, Miyairi T, Morota T, Shibata
K, Murakami A, Kotsuka Y: Arterial blood gas management in retrograde cerebral perfusion: the importance of carbon dioxide. Eur J Cardiothorac Surg. 20,
979-85, 2001.
44. Takeshi Miyairi, Yutaka Kotsuka, Tetsuro Morota,
Hiroshi Kubota, Ko Shibata, Yorinobu Ikeda, Tadashi
Kitamura, Takeshi Kashima, Shinichi Takamoto:Paraplegia after open surgery using endovascular
stent grafting for aortic arch. J Thorac Cardiovasc
Surg 122: 1240-3, 2001.
45. Takeshi Miyairi, Shinichi Takamoto, Yutaka
Kotsuka, Arata Murakami, Hiroshi Kubota, Toshiya
Ohtsuka: Strategy for redo surgery on the thoracic
aorta. Keio University International Symposia forLife Science and Medicine, Ed by S. Kawada, Vol. 7:
90-98, 2001. Tokyo.
46. Suematsu Y. Takamoto S. Ohtsuka T. Intraoperative
echocardiographic imaging of coronary arteries andgraft anastomoses during coronary artery bypass
grafting without cardiopulmonary bypass. J Thorac
Cardiovasc Surg 122, 1147-54, 2001.
47. Murakawa T, Nakajima J, Motomura N, Murakami
A, Takamoto S.: Successful allotransplantation of
cryopreserved tracheal grafts with preservation of
the pars membranacea in nonhuman primates. J
Thorac Cardiovasc Surg 123, 153-60, 2002.
48. Kubota H, Takamoto S, Murakami A, Kotsuka Y, &Furuse A: Biologic glue-molded “bio-mini-paddle”
electrode used for atrial and ventricular pacing anddefibrillation. Ann Thorac Surg 322-4, 2002.
49. Kotsuka Y, Ezure M, Tanaka K, Takamoto S,
Kuwahara K, Ikeda H. Ultrathin-wall vascular grafts
for endovascular surgery. J Art Org 5: 108-112, 2002．
50. Suematsu Y. Ohtsuka T. Miyairi T. Motomura N.
Takamoto S. Ultrasonic evaluation of graft anastomoses during coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 74,
273-5, 2002.

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Department of
Gastrointestinal Surgery /Department of Surgical
Metabolism and Nutrition and
Endocrine Surgery
Outline and Research Objectives
Since 2001, the former Third Department of Surgery, which was located in a branch hospital of the University of Tokyo, has been divided into two departments, the Department of
Gastrointestinal Surgery and the Department of Surgical Metabolism and Nutrition and
Endocrine Surgery, in line with the integration of the main and branch hospitals the elevation to a department in the graduate school of medicine at our university. Our research
activities in both departments have been well organized and ultimately successful by maintaining a close connection.
The main research activities of the department of Gastrointestinal Surgery are focusedon diagnosis and therapy for gastrointestinal diseases and clinical and basic research forgastrointestinal carcinogenesis. A historical and outstanding achievement of the department
of Gastrointestinal Surgery is the successful innovation of the “Gastrocamera” a half century
ago. Thereafter, we have been active in the diagnosis and treatment of gastric cancer andestablished the feasibility of extended gastrectomy with intraoperative chemotherapy foradvanced cancer, and limited lymph node dissection for early gastric cancer. With a view tofurther development of research for gastrointestinal carcinogenesis, we established theJapanese Society for Gastroenterological Carcinogenesis in 1989, and have been studying
the underlying mechanisms of development, progression and prevention of digestive cancer.
The department of Surgical Metabolism and Nutrition and Endocrine Surgery has been
studying one of the most fundamental issues in surgery, i.e., “surgical stress,” which indicates postoperative physiological and endocrinological internal reaction, and nutritional support for the postoperative patients. Our department is a pioneer in this area in Japan, andwe established the Japanese Society for Surgical Metabolism and Nutrition in 1965. In addition, we have been studying endocrine issues, i.e., surgical therapy for breast, thyroid andparathyroid diseases.

Faculties and Students

Past Research and Major Accomplishments

Professor and Chairman Michio Kaminishi, MD., Ph.D.
(since 1997)
Associate Professor Ken-ichi Mafune, MD., Ph.D.
(Yoshikazu Mimura, M.D., Ph.D.
from Division of Surgical
Operation Center)
Lecturer
Shouji Shimoyama, MD., Ph.D.
Toshihisa Ogawa, MD., Ph.D.,
Mitsue Saito MD., Ph.D.,
Associate ...............................12
Postdoctor Fellow ...................8
Graduate Student....................9
Secretary .................................4

In research on gastrointestinal carcinogenesis, wehave established experimental models of gastric carcinogenesis and looked closely at the important rolesof repetition of injury and regeneration of gastricmucosa. In particular, we demonstrated that infectionof Helicobacter pylori acts not only in promotion but
also in co-initiation of gastric carcinogeneis. This was
the first report in the world to show the direct relationship between H.p. infection and gastric carcinogenesis using experimental models. Furthermore, we
verified that duodenogastric reflux and denervation of
the gastric mucosa enhance gastric mucosal injury,
resulting in development of gastric remnant cancer.

228

Based on these results, we have adopted new operations for gastric cancer and obtained better results interms of postoperative QOL and outcome. Ourdetailed histopathological analysis of colon carcinogenesis revealed de novo carcinogenesis other thanadenoma-carcinoma sequence, leading to the current
hypothesis of the dysplasia-carcinoma sequence.
In research on surgical metabolism and nutrition,
we clearly showed the importance of nutritional support under condition of postoperative hypoxia andendotoxemia. Fatty acids reduced the morbidity andmortality due to panperitonitis, and glutamine attenuated acute lung injury after the organism was challenges with endotoxin. Research on the metabolismof phosphate, calcium and sodium is one of the mostimportant means to clarify the mechanism of the
postoperative physiological reaction. We demonstrated the close relationship between these metabolites
and catecholamine after surgical stresses such as
hypoxia, endotoxiemia and ischemic reperfusion
injury. These studies aim to reduce the intra- andpost-operative stresses that would be risky forpatients.

Current Research
The main focus of our current research in the fieldof Gastrointestinal Surgery is the tailor-made treatment of cancer based on its stage and characteristics.
We try to establish the optimal limited surgery forearly cancer by application of sentinel node navigation system and molecular analysis of lymph node
micrometastasis. For advanced cancer, multimodal
therapy combined with extended surgery and perioperative chemotherapy is required. In regard tochemotherapy, a new strategy using apoptosis-related
and/or cell differentiation-related agents is likely toachieve better prognosis in advanced cases.
Current research topics in the department of
Gastrointestinal Surgery are the followings.
1) Carcinogenesis of gastrointestinal cancer･ Roles of Helicobacter pylori infection in gastriccarcinogenesis･ Roles of Trefoil Peptides in gastric metaplasia･ Clinical and experimental studies on Barrett
esophagus
2) Molecular mechanisms of gastrointestinal cancer･ Effects of hypoxia and nutritional deprivation on
cancer development and progression･ Roles of PPARr in gastric carcinogenesis and treatment of gastric cancer by PPARr ligands･ Angiogenic factors in gastrointestinal cancer･ Telomerase activity in gastrointestinal tumors･ Lymph node micrometastasis of gastric cancer

3) Minimally invasive treatment of upper GI cancers･ Indication and results of laparoscopic surgery･ Sentinel node navigation surgery for early gastriccancer･ Evaluation of results of PPG and jejunal interposition after gastrectomy in terms of postoperative
QOL4) Multimodal treatment for esophageal and gastric cancers･ Neoadjuvant or definitive chemoradiation therapy
for esophageal cancer･ Apoptosis induced by TRAIL･ Prediction of gastric cancer recurrence by molecular analysis of samples of peritoneal washes･ Mechanisms of adverse effects of chemotherapy
for gastrointestinal cancer on the intestinal
mucosa and its preventive therapy5) Gastrointestinal motility･ Mechanism of peppermint oil solution on relaxation of digestive tract･ Role of cytokine and COX-2 in gastrointestinal
motility･ Effects of intra- and extra-abdominal environments on gastrointestinal motility･ Gastric motility after gastrectomy
The main focus of our current research in the fieldof Surgical Metabolism and Nutrition is “adaptive
response to surgical stresses”. In particular, “cross tolerance among different stresses” is a very challenging
and important phenomenon to be elucidated, and theclinical application of findings will lead to reductionof morbidity and mortality due to severe surgicalstresses and endotoxin shock. On the other hand,
there is a definite difference in adaptive response tosurgical stress between genders. We have clearly
demonstrated the gender difference in cytokine secretion after endotoxin challenge.
In the field of Endocrine Surgery, we have introduced minimally invasive surgery for breast cancer
and thyroid tumors through the application of laparoscopic procedures. In terms of differential diagnosis of
thyroid tumors, we established a method for the
immunohistochemical detection of telomerase
reverese ranscriptase (hTERT) by in situ hybridization, providing a good marker for distinction between
follicular adenoma and follicular cancer.
Current research topics in the department ofSurgical Metabolism and Nutrition and Endocrine
Surgery are the followings2291) Surgical metabolism and nutrition･ Mechanisms of cross tolerance among different
stresses (endotoxin-hypoxia/ hypoxia-endotoxin)
after surgery･ Role of catecholamines in adaptation to surgicalstress such as endotoxemia･ Bacterial translocation after major surgery andanti-cancer chemotherapy･ Gender difference is a modulation factor for postoperative morbidity･ Parathyroid function after surgical stress･ Ischemic preconditioning and its underlying
mechanism (NO, HSP, metalothionein)
2) Endocrine surgery･ Cytology of breast and thyroid tumors by in situ
hybridization of telomerase reverse transcriptase(hTERT)･ Effects of preoperative endocrine therapy of breast
cancer･ Detection of breast cancer cell in the drainage vein
from the breast by using RT-PCR･ Molecular analysis of heterogeneity in breast andthyroid cancers･ Development of QOL questionnaire for breast cancer patients

Future Prospects (Figure 1)
Our main theme in basic and clinical research is“Surgery and Inflammation”. There are 2 phases of230

inflammation, acute and chronic. Under acute inflammation or acute stress, injured tissue recovers to normal promptly after subsidence of the acute causes. In
that case, the organ represses apoptosis and maintains or restores the normal tissue. Many factors suchas cytokines, NO, NF-κB, and HSP play importantroles in development and progression of the inflammatory process. Conversely, these molecular factors
play a key role in the attenuation of morbidity
through across tolerance mechanism. Clinical application of therapy based on cross tolerance leads to a better prognosis for morbid patients after severe surgicalstress.
Under chronic inflammation, for, example, In
cases of chronic gastritis, however repetition of injury
and subsequent regeneration is observed regardless ofthe causes. The accelerated regeneration of the gastricmucosa induces a newly developed tissue that is
adapted for chronic injury by balancing cell proliferation and apoptosis. This phenomenon is widely recognized as metaplasia and all metaplastic change in thehuman organ is considered to be a result of adaptive
reaction. Furthermore, the metaplastic cells and/or thecells departing from the adaptive process have potential for malignant transformation.
The relation between chronic inflammation andcarcinogenesis is commonly observed not only in thestomach, but also in the esophagus, colon, liver andother tissues. Examples include reflux esophagitis andBarrett’s cancer, ulcerative colitis and colitic cancer,
viral hepatitis and hepatoma. Some key factors suchas NF-kB, COX, NO, PPARr, HSP, and trefoil peptides
play important roles in the process of chronic inflammation. In addition, those factors are also expressedin breast and thyroid tumors.
The development of molecular biology-based diagnosis for cancers and the tailor-made treatment forcancer patients depending on the properties of eachcancer and each patient’s genetic background, areurgent issues. Further analysis of the relevant factors
may contribute to advances in diagnosis, treatment
and prevention of not only gastrointestinal cancers
but also breast and thyroid cancers. In particular,
PPARr, trefoil peptide and histone deacetylase
inhibitors (HDAIs) modulate not only cell proliferation but also cell differentiation. We are trying todevelop a new strategy of molecular targeting therapy
for gastrointestinal, breast and thyroid cancers byapplication of these cell-differentiating factors.

Research Grants
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Clonal analysis of isolated intestinal metaplastic
glands of stomach using X linked polymorphism
Quantitative detection of micrometastases in thelymph nodes of gastric cancer patients with real-time
RT-PCR
Histopathological change and expression of genes
and proteins in chief cells through gastric carcinogenesis in rodent models
Sublethal endotoxin administration evokes superresistance to systemic hypoxia.
Telomeres and telomerase activity in digestive andendocrine organs: Clinical application to the diagnosis and therapy.

Select Publications
1. Kaminishi M, Sadatsuki H, Johjima Y, Oohara T,
Kondo Y. A new model for production of chronic
gastric ulcer by duodenogastric reflux in rats.
Gastroenterology 92, 1913-1918,1987.
2. Mimura Y, Yamakawa M, Furuya K, Oohara T. Effectof oxygen supply on protein metabolism in surgicallyinjured rats-oxygen as a nutrient. Ann Surg 212,228233,1990.
3. Maeda J, Dudrick SJ. Rapid spectrophotometricdetermination of plasma carnitine concentrations.
JPEN 14, 527-532,1990.
4. Mimiura Y, Khraibi AA, Heublein DM, Knox FG.
Acute hypoxia blunts natriuretic and diuretic effcets
of atrial natriuretic factor in rats. Am J Physiol 266,103-1509,1994.
5. Shimoyama S, Kaminishi M, Joujima Y, Oohara T,
Hamada C, Teshigawara W. Lymph node involvement correlation with survival in advanced gastriccarcinoma: Univariate and multivariate analysis.
Journal of Surgical Oncology 57, 164-170,1994.

6. Kaminishi M, Shimizu N, Shimoyama S, Yamaguchi
H, Ogawa T, Sakai S, Kuramoto S, Oohara T.
Etiology of gastric remnant cancer with special reference to the effects of denervation of the gastricmucosa. Cancer 75, 1490-1496,1995.
7. Hiki N, Berger D, Buttenschoen K, Boelke E,
Seidelmann M, Strecker W, Kind L, Beger HG.
Endotoxemia and specific antibody behaivior against
different endotoxins following multiple injuries. J
Trauma 38, 794-801,1995.
8. Kaminishi M, Shimizu N, Nomura S, Ohkura F,
Shimoyama S, Yamaguchi H, Hashimoto M, Ogawa
T, Sakai S, Oohara T. Different carcinogenesis in thegastric remnant following gastrectomy for gastriccancer. Cancer 77, 1646-1653, 1996.
9. Nomura S, Kaminishi M, Sugiyama K, Oohara T,
Esumi H. Clonal analysis of isolated single fundic
and pyloric gland of stomach using X -linked polymorphism. Biochem Biophy Res Commun 226,385390,1996.
10. Nakamura T, Yamakawa M, Maeda J, Mimura Y,
Yamada H, Ogawa T, Kanauchi H, Oohara T. Effectof glutamin on acute lung injury in rats with endotoxemia. Clinical Nutrition 16,79-83,1997.
11. Kanauchi H, Mimira Y. Adrenalectomy overcomes
the blunted natriuretic response to atrial natriuretic
peptide during hypocapnia in rats. Clin Exp
Pharmacol Physiol 24,850-855,1997.
12 Kuramoto S, Mimura T, Yamazaki K, Kobayashi K,
Hashimoto M, Sakai S, Kaminishi M, Oohara T. Flat
concers do develop in the polyp-free large intestine.
Dis Colon Rec 40,534-542,1997.
13. Shimizu N, Kuramoto S, Mimura T, Kobayashi K,
Kobayashi M, Sakai S, Kaminishi M, Oohara T.
Helicobactor pylori promotes development of
pepsinogen altered pyloric glands, a prreneoplastic
lesion of glandular stomach. Cancer Letter 27, 546549,1997.
14. Kaminishi M, Yamaguchi H, Shimizu N, Nomura S,
Yoshikawa A, Hashimoto M, Sakai S, Oohara T.
Stomach-partitioning gastrojejunostomy for unresectable gastric carcinoma. Arch Surg 132,184187,1997.
15. Nomura S, Kaminishi M, Sugiyama K, Oohara T,
Esumi H. Clonal analysis of isolated intestinal metaplastic gland of stomach using X-linked polymorphism. Gut 42. 663-668, 1997.
16. Hiki N, Beger D, Boelke E, Nussler A, Seidelmann M,
Braumueller HD, Oohara T, Beger HG. Endotoxin
elimination by human monocytes-endotoxin is neutralized via CD14? Shock 7,22-23,1997.
17. Mimura Y, Yamakawa M, Maeda J, Tateno I, Araki S,
Fujita T, Sugizaki K, Furuya K, Oohara T. Efficacy ofamino acid infusion for improving protein metabolism after surgery-A prospective randomized study inpatients undergoing subtotal gastrectomy. J Am Coll
Surg 185,163-171,1997.
18. Hiki N, Berger D, Boelke CPE, Wiedeck H,
Seidelmann M, Staib L, Oohara T, Kaminishi M,
Beger HG. Endotoxin binding and elimination by231monocytes: the secretion of soluble CD14 represents
an inducible mechanism counteracting reduced
expression of membrane CD14 during sepsis and ina patient with paroxysmal nocturnal hemoglobinuria. Infect Immun 66, 1135-1141,1998.
19. Kanauchi H, Yamasaki K, Ogawa T, Mimura Y.
Endoscopic thyroidectomy in a porcine. Endocrine J
45,135-136,1998.
20. Sugiyama A, Maruta F, Ikeno T, Ishida K, Kawasaki
S, Katsuysma T, Shimizu N, Tatematsu M.
Helicobacter pylori infection enhances MNU (Nmethyl-N-nitrosourea)-induced stomach carcinogenesis in the Mongolian Gerbil.Cancer Res 58, 20672069,1998.
21. Zhang D, Shimoyama S, Kaminishi M. Feasibility ofpylorus-preserving gastrectomy with a wider scopeof lymphadenectomy. Arch Surgery 133,993997,1998.
22. Shimizu N, Inada K, Nakanishi H, Tsukamoto T,
Ikehara Y, Kaminishi M, Kuramoto S, Sugiyama A,
Katsuyama T, Tatematsu M. Helicobacter pylori
infection enhances glandular stomach carcinogenesis
in Mongolian gerbils treated with chemical carcinogens. Carcinogenesis 20, 669-676,1999.
23. Shimoyama S, Shimizu N，Kaminishi M. Type-oriented intraoperative and adjuvant chemotherapy andsuvival after curative resection of advanced gastriccancer. World J Surg 23,284-292, 1999.
24. Shimoyama S, Yamasaki K, Kawahara M, Kaminishi
M. Increased angiogenin concentration in colorectal
cancer is correlated with cancer progression. ClinicalCancer Res 5,1125-1130, 1999.
25. Mafune K, Tanaka Y. Influence of multimodality
therapy on the cellular immunity of patients withesophageal cancer. Ann Surg Oncol 7,609-616, 2000.
26. Nakamura K, Furugori E, Esaki Y, Arai T, Sawabe M,
Okayasu I, Fujiwar M, Kammori M, Mafune K, Kato
M. Correlation of telomere lengths in normal andcancers tissue in the large bowel. Cancer Lett
158,179-184, 2000.
27. Shimizu N, Ikehara Y, Inaba K, Nakanishi H,
Tsukamoto T, Nozaki K, Kaminishi M, Kuramoto S,
Sugiyama A, Katsuyama T. Eradication Diminishes
Enhancing Effects of Hellicobactor pylori Infection
on Glandular Stomach Carcinogenesis in Mongolian
Gerbils. Cancer Res 60, 1512-1514, 2000.
28. Shimoyama S, Kaminishi M. Increased angiogenin
expression in gastric cancer correlated with cancer
progression. J Cancer Res Clin Oncol 126, 468-474,
2000.
29. Seto Y, Takenoue T, Nariko H, Kaminishi M.
Influence of gastrectomy on the distribution of intravenously administered 5-fluorouracil to regional
lymph nodes in an animal model. Cancer 88,24432446, 2000.
30. Shimoyama S, Aoki F, Murakami T, Toyoda K,
Kaminishi M. The feasibility of daily concurrent
chemoradiation therapy as a nonsurgical management for esophageal cancer: Our experience and the-232

oretical backgrounds. J Surg Oncol 74, 134-137,
2000.
31. Shimoyama S, Seto Y, Yasuda H, Kaminishi M.
Wider indications for the local resection of gastriccancer by adjacent lymphadenectomy. J Surg Oncol,
75, 157-164, 2000.
32. Takahashi K, Saito M, Makita M, Tada T, Uchida Y,
Yoshimot M, Kasumi F, Akiyama F, Sakamoto G.
Surgery for ductal carcinoma in situ. Breast Cnacer
7,337-340, 2000.
33. Hiki N， Berger D， Mimura Y， Frick J, Dentener
MA， Buurman WA，Seidelmann M，Kaminishi
M， Beger HG. Endotoxin binding proteins during
major elective surgery: role of sCD14 for phagocytic
activation. World J Surg 24,499-506, 2000.
34. Kanauchi H, Mimura Y, Hiki N, Kaminishi M.
Catecholamine and cytokine response to laparoscopic adrenalectomy in patients with pheochromocytoma. Biomed Pharmacother 54,191-193, 2000.
35. Kammmori M, Takubo K, Nakamura K, Furugouri E,
Endo H, Kanauchi H, Mimura Y, Kaminishi M.
Telomerase activity and telomere length in benign
and malignant human thyroid tissues. Cancer Lett
159,175-181, 2000.
36. Ogawa T, Mimura Y, Hiki N, Kanauchi H, Kaminishi
M. Ischaemic preconditioning ameliorates functional
disturbance and impaired renal perfusion in rat
ischaemia-reperused kidneys. Clin Experimental
Pharmacol Physiol 27,997-1001, 2000.
37. Ogawa T, Nussler AK, Tuzuner E, Neuhaus P,
Kaminishi M, Mimura Y, Beger HG. Contribution of
nitric oxide to the protective effects of ischemic preconditioning in ischemia-reperfused rat kidneys. J
Lab Clin Med 138, 50-58, 2001.
38. Imamura K, Ogura T, Kishimoto A, Kaminishi M,
Esumi H. Cell Cycle Regulation via p53
Phosphorylation by a 5’-AMP Activated Protein
Kinase Activator, 5-Aminoimidazole-4-Carboxamide1-β-Ribofuranoside, in a human Hepatocellular
Carcinoma Cell Line. Biochem Biophy Res Commun
287, 562-567, 2001.
39. Kammori M, Kanauchi H, Nakamura K, Kawahara M,
Weber T, Mafune K, Kaminishi M, Takubo K.
Demonstration of human telomerase reverse transcriptase in human colorectal carcinomas by in situ
hybridization. Int J Oncol 20,15-21, 2001.
40. Seto Y, Yamaguchi H, Shimoyama S, Shimizu N,
Aoki F, Kaminishi M. Results of local resection with
regional lymphadenectomy for early gastric cancer.
Am J Surgery 182, 498-501, 2001.
41. Kawahara M, Kammori M, Kanauchi H, Noguchi, C
Kuramoto S, Kaminishi M. Immunohistochemical
prognostic indicators of gastrointestinal carcinoid
tumors. Eur J Surg Oncol 28, 140-146, 2001.
42. Asai K, Hiki N, Mimura Y, Ogawa T, Unou K,
Kaminishi.M. Gender differences in cytokine secretion by human peripheral blood mononuclear
cell:role of estrogen in modulating lps-induced
cytokine secretion in an EX VIVO septic model.
Shock16, 340-343, 2001.

43. Kammori M, Mafune K, Kawahara M, Mimura Y,
Kaminishi M, Takubo K. Telomere shortening withaging in human thyroid and parathyroid tissue.
Experiment Gerontol 37,513-521, 2002.
44. Kammori M, Nakamura K, Kamnauchi H, Obara T,
Kawahara M, Mimura Y, Kaminishi M, Takubo K.
Consistent decrease in telomere lemgth in parathyroid tumors but alteration in telomere activity limited to malignancies: Preliminary report. World J Surg
26,1083-1087, 2002.
45. Nozaki K, Shimizu N, Tsukamoto T, Inada K, Cao X,
Ikehara Y, Kaminishi M, Sugiyama A, Tatematsu M.
Reversibility of Heperotopic Proliferative Glands in
Glandular Stomach of Helicobacter pylori-infected
Mongolian Gerbils on Eradication. Jpn J Cancer Res
93,374-381, 2002.
46. Li QL, Ito K, Sakakura C, Fukumachi H, Inoue K, Chi
XZ, Kaneda A. Causal relationship between the loss
of RUNX3 expression and gastric cancer. Cell
109,113-124, 2002.
47. Kaneda A, Kaminishi M, Nakanishi, Y Sugimura T,
Ushijima T. Reduced Expression of the InsulinInduced Protein 1 and p41 ARP2/3 Complex Genes in
Human Gastric Cancers. Int J Cancer 100, 57-62,
2002.
48. Yamaguchi H, Goldenring JR, Kaminishi M, Lee JR.
Identification of Spasmolytic Polypeptide Expressing
Metaplasia(SPEM) in Remnant Gastric Cancer andSurveillance Postgastrectomy Biopsies. Dig Dis
Science 47,573-578, 2002.
49. Shimoyama S, Kaminishi M. Supra-additive antitumor activity of 5FU with tumor necrosis factor related apoptosis inducing ligand on gastric and coloncancers in vitro. Int J Oncol 21,643-648, 2002.
50. Yamaguchi H, Goldenring JR, Kaminishi M, Lee JR.
Association of spasmolytic polypeptide-expressing
metaplasia with carcinogen administration andoxyntic atrophy in rats. Lab Invest 82:1045-1052,
2002

233

Department of Hepato-BiliaryPancreatic Surgery /Department of Artificial
Organ and Transplantation
Outline and Research Objectives
In September 1893, Professor Sankichi Satoh founded “the Second Department ofSurgery, University of Tokyo”. He was a pioneer of visceral surgery in Japan and he also
founded the Japanese Society of Surgery in 1899. His pupils, professor Waichiroh Okada,
professor Keizo Doi, professor Hisashi Ishihara founded departments of otorhinolaryngology, dermatology, and dental surgery, respectively at Unversity of Tokyo Hospital.
In May 1952, professor Seiji Kimoto became the 5th chairman of our department. He wasa pioneer of cardiovascular surgery in Japan, and founded the department of thoracic surgery in 1964. In the same year, he also performed the first case of kidney transplantation in
Japan.
In July 1971, professor Shigeru Hatano, the 6th chairman, founded the department ofPediatric Surgery.
In April 1994, I (professor Masatoshi Makuuchi) became the 10th chairman. I started living donor liver transplantation on January 31st, 1996 and has done 191 cases by the end of
September 2002. As the result of the shift to the Graduate School of Medicine, the three
Departments of Surgery were transformed to one Department and 6 divisions in April 1998.
Our second Department of Surgery took charge of “Hepato-Biliary-Pancreatic Surgery
Division, andArtificial Organ and Transplantation Division”.
Our current main research objectives are surgical treatment of hepato-biliary-pancreaticcancer, liver transplantation, and development of artificial liver.

Faculties and Students
Professor and Chairman Masatoshi Makuuchi, MD,
PhD (1994-)
Associate Professors Norihiro Kokudo, MD
Yasuhiko Sugawara, MD
Lecturer
Hiroshi Imamura, MD
Associate ...............................11
Postdoctal Fellow....................5
Graduate student ....................9
Research student.....................2
Secretary .................................4

Past Research and Major Accomplishments
Between late 1970’s and early 1980’s, I have developed the application of ultrasound to the various
treatment modalities of hepatobiliary diseases. First, I
have developed the percutaneous transhepatic cholangiography (PTC) and the percutaneous transhepatic
biliary drainage (PTBD) method under ultrasoundguidance. With these methods, intrahepatic biliary
tract was punctured selectively and drainaged directly
by real-time guidance. Ultrasound-guided PTC and

234

PTBD methods are simple and easy to perform andnow are widely used over the world. I also investigated precisely the anatomy and its variation of theintrahepatic portal branches for the first time by theultrasound examination. Before this work, information on its anatomy was obtained mainly by the studyof the cadaveric liver which was somewhat mal
understood or by the angiographic studies which byitself does not allow a precise evaluation on eachpatients. I then developed an intraoperative ultrasound probe and it was facilitated liver surgery for the
first time in the world. By its usage, the positional
relationship between the tumor and intrahepatic vasculobiliary structure can be understood during thehepatic parechymal transection. This is particularly
important in liver resection in cirrhotic liver because
the examination of the tumor by bimanual palpation
is difficult in such cases. Further, I developed themethod to resect anatomically the Couinaud’s segment by the aid of ultrasound and so-called staining
technique of the intrahepatic portal branch. This
small but anatomical resection is now accepted as astandard procedure for the patients with hepatocellular carcinoma de facto and called also as ‘Makuuchi’sprocedure’. Based on the findings of the liver anatomy, I have developed and performed, besides theabove described anatomical resection, central bisectorectomy or right paramedian sectorectomy. This canbe considered a remarkable advance in the era whensolely the right or left hepatcetomy was performed as
anatomical hepatc resections.
Development and application of intermittent
hemihepatic or total inflow occlusion technique is alsoa fruit of my effort in this period. In 1980’s, total
inflow occlusion was sporadically carried out over theworld. But it was used always as a continuous mannerand maximum length of the occlusion was considered
60 minutes. Moreover, it was almost a central dogmathat the cirrhotic liver could not tolerate the inflow
ischemia. Since intermittent ischemia was a recycle ofischemia/reperfusion injury it was believed to beworse than continuous ischemia. In these circumstances, I, for the first time, proved the inflow occlusion can be applied to cirrhotic liver and intermittent
inflow occlusion can be applied safely and better thancontinuous occlusion technique.
The development of various operative procedures
preserving the thick short hepatic vein as a drainage
vein of right lateral sector and scarifying the righthepatic vein is the achievement of this period. In
addition, I first demonstrated the right hepatic veincan be safely divided and ligated extrahepatically if
the inferior vena cava ligament was divided and cut
prior to the dissection. These vein and ligament are
now called as ‘Makuuchi’s vein’ and ‘Makuuchi’s ligament’ worldwide.
Extended right hemihepatectomy is often necessary in the surgical treatment of hilar cholangiocarcinoma. Such a procedure may lead to the increased
risk of postoperative liver insufficiency. I have developed and applied the preoperative portal vein
embolization (PVE) to induce the atrophy of the liver
to be resected and thus induce the compensatory
hypertrophy of the liver part to be preserved after theresection. In 1982, I performed the first case of PVE inthe world. This method is simple to apply and now is
widely applied all over the world.
By virtue of the development of these procedures
and improvement in the technical skill, the operative
mortality of liver resection in my institute is almost
zero including that for the cirrhotic liver and for thehilar cholangiocarcinoma compromized with obstructive jaundice.
In June 1990, I started living donor liver transplantation (LDLT). Based on my own experience of LDLT,
I have proposed a formula that allows the calculationof the ideal liver volume to the recipient or the donor
used the preoperative decision of what kind of donor
hepatectomy should be performed. This formula is
now called as ‘Makuchi’s formula’. In 1993, I per-formed successfully for the first time in the world theadult-to-adult LDLT using left hemiliver. Following
this success, I have carried out adult-to-adult LDLT
including emergency transplantation for patients withfulminant hepatic failure. The number of patients
undergoing LDLT until now exceeds 200 cases withless than 10 % overall mortality. Recent my contribution to this field is the establishment of the feasibilityof the right lateral sector graft and the establishmentof the criteria for reconstruction of the middle hepatic
venous tributaries in case of right hemiliver graft.

Current Research
I have established a safe and effective hepatic
resection techniques based on the liver anatomy andchallenged repeated hepatic resections for recurrent
liver tumors including hepatocellular carcinoma (HCC)and metastatic tumors. As one of the top institutes ofhepato-biliary surgery in the world, we have achieved
no mortality and minimum morbidity hepatic resection in recent series of patients, and we have encouraged surgeons worldwide. The accumulated clinicaldata will reveal the long-term results that demonstrate the advantages of surgical treatment for liver
tumors. The molecular biological investigations ofliver tumors will elucidate the biological behaviors
and prognostic factors of these malignant diseases.
However, there are a number of patients with HCC
who are not candidates for hepatic resection becauseof the limited liver functional mass. Since Milan groupreported promising results of orthopic liver transplantation for HCC in selected cases, I have started living
donor liver transplantation (LDLT) for recurrent HCC.
As one of the treatment options for HCC, LDLT will
be commonly performed in Japan. The indications for
cadaveric liver transplantation for HCC have been limited because of donor shortage. I am trying to expand
the indications of LDLT for HCC beyond the Milancriteria. The long-term results may clarify the indications for LDLT for HCC.
Strong and co-workers reported the first successfultransplantation from a living donor (LDLT). LDLT ismainly conducted in an attempt to alleviate the shortage of donor organs and to decrease mortality amongchildren awaiting transplants. I started the LDLT program in 1990 when I was in Shinshu University. The
indications of LDLT expanded to the adults and I performed the first successful case in 1994. After I
moved to University of Tokyo, I started the programin 1996. Until September 2002, I accumulated 191
cases. The mortality rate of the patients is less than
10%, which is much superior to the world standard.
The major limitation for LDLT for adults is theadequacy of the graft size. To overcome this problem,
I devised the left liver plus caudate lobe graft with its

235

venous reconstruction. The caudate lobe can provide
about a 7% increase in graft weight, which contributed
the less frequent cholestasis after the operation. The
right liver graft is now most commonly used graft in
LDLT for adults. The right liver graft is usually harvested without the trunk of the middle hepatic vein.
However, this type of grafts can cause severe congestion of the right paramedian sector because middle
hepatic vein often drains the considerable part of this
sector. Middle hepatic vein drainage into the recipient’s venous system can be reconstructed using vein
grafts. This provides a functioning liver mass comparable to an extended right liver graft. I firstly proposed reconstruction criteria.
Right liver harvesting from living donors is sometimes dangerous when the volume ratio of right liveris large. Some donors have larger right lateral sector
compared with left liver. I firstly performed LDLT
suing this type of graft.

List of On-going Research Projects
1) Hepato-pancreato-biliary surgery
Extended hemihepatectomy for hilar bile duct carcinoma
Development of ultrasonic diossector equippedwith electrocautery
Liver resection of liver metastases from GIST
Long-term evaluation of two-staged pancreaticoduodenectomy
Intraoperative ultrasound-guided direct pancreatography
Liver hypertrophy after hepatopancreatoduodenectomy
Resection of S4inf during hepaticojejunostomy
Reconstruction of superior mesenteric vein using
cryopreserved homograft vein
Repeated hepatic resection for colorectal metastases
Risk factors for biliary leakage after liver resection
Arterial buffer response in cirrhotic patients
Evaluation of hepatic functional reserve using GSA
scintigraphy
Resection of IVC wall and/or root of hepatic veinin colorectal metastasis
Effect of cimetidine on the postoperative recurrence in HCC patients
Disruption of pRb-p16 INK4 pathway: a common
event in ampullary carcinogenesis
Qualitative and quantitative analysis of desgamma-carboxy prothrombin (DCP) in cancerous
and non-cancerous liver tissue of patients with
HCC
Protein induced by Vitamin K absence or antagonist II absence (PIVKA-II) in cancerous and non-236

cancerous liver tissue of patients with HCC
Serum anandamide levels in infection
2) Transplantation
Diagnostic criteria for fungal infection in posttransplant patients
Quality of life in donors for LDLT
Argorythms for the timing of liver biopsy after
LDLT
Effect of hANP in post-transplant oliguria
Serological marker for early detection of carinii
pneumonia
Reconstrucrion of venous tributaries in right livergraft (long-term outcome)Re-evaluation of the Milan’s criteria for the indication of cadeveric livertransplantation to patients with hepatocellular carcinoma
Donor inflow occlusion technique in living donorliver transplantation
Liver regeneration in donors
Development of anti-septic biliary drainage tube
for LDLT
3) Artificial Organ
Artificial liver for xeno-cross circulation and clinical application
Artificial liver and transgenic pig for clinical application
Development of artificial erythrocyte for liver support system
Reconstruction of liver tissue using bone marrowtransplantation

Future Prospects
Beyond the technical challenges are various medical issues that perhaps need to be given greater attention in the future. LDLT has come to address a healthconcern of epidemiologic dimension in Japan, namely
hepatitis B and C and consequently occurred hepatocellular carcinoma. Recurrent disease after liver transplantation remains a major threat and efforts aimed atprevention and cure have to continue.
Issues related to immunosuppression have to be
tackled and induction or facilitation of graft tolerance,
which may not be as elusive in LDLT, is yet to beachieved. Management of infection in the immunosuppressed transplant patient is a peculiar challengethat transplant specialists must face in the near
future.
Research project of artificial liver device is almost
close to clinical use for the bridge to liver transplantation for the patients with liver failure. Recent advanceof research about the regeneration medicine has
demonstrated the possibility of hepatocyte differenti-

ation from bone marrow or embryonic stem cells. For
the treatment of fulminant liver failure, the humanhepatocytes cultured and expanded from bone marrow will be used in the future.

Research Grants
1999-2001 Improvement of surgical treatment for biliary
cancer.
Grant for the prevention of cancer, the ministry ofhealth and labor
4,800,000 yen
1999-2001 Artificial liver for xeno-cross circulation andclinical application
Grant from the ministry of education and science(A)(2)
35,800,000yen
2000-2001 Clinical improvement and development oforgan transplantation
Grant for the human genome and regeneration, theministry of health and labor
4,500,000 yen
2000-2001 Research on intractable liver disease
Grant for intractable diseases, the ministry of healthand labor
1,000,000 yen
2001-2002 Artificial liver and transgenic pig for clinicalapplication
Grant for advanced medicine (A), the ministry ofhealth and labor
196,840,000 yen

Select Publications
1. Makuuchi M, Bandai Y, Ito T, Wada T: Ultrasonicallyguided pancreatography. Radiology 134:767-770,
1980.
2. Makuuchi M, Bandai Y, Ito T, Watanabe G, Wada T,
Abe H, Muroi T: Ultrasonically guided percutaneoustranshepatic bile drainage: A single step procedure
without cholangiography. Radiology 136:165169,1980.
3. Makuuchi M, Hasegawa H, Yamazaki S, Bandai Y,
Watanabe G, Ito T: The inferior right hepatic vein :ultrasonic demonstration. Radiology 148:213-217,
1983.
4. Makuuchi M, Hasegawa H, Yamazaki S Moriyama N,
Takayasu K, Okazaki M: Primary Budd-Chiari syndrome: ultrasound demonstration. Radiology
152:775-779, 1984.
5. Makuuchi M, Sukigara M, Mori T, Kobayashi J,
Yamazaki S, Hasegawa H, Moriyama N, Takayasu K,
Hirohashi S: Bile duct necrosis: complication of transcatheter hepatic arterial embolization. Radiology
156:331-334, 1985.
6. Makuuchi M, Hasegawa H, Yamazaki S:
Ultrasonically guided subsegmentectomy. Surgery,
Gynecology & Obstetrics 161:346-350, 1985.
7. Gunven P, Makuuchi M, Takayasu K, Moriyama N,
Yamasaki S, Hasegawa H: Preoperative imaging ofliver metastases - comparison of angiography CT
scan and ultrasonography. Annals of Surgery
202:573-579, 1985.
8. Makuuchi M, Hasegawa H, Yamazaki S, Takayasu K:
Four new hepatectomy procedures for resection of
the right hepatic vein and preservation of the inferior
right hepatic vein. Surgery, Gynecology & Obstetrics
164:68-72, 1987.
9. Makuuchi M, Mori T, Gunvén P, Yamazaki S,
Hasegawa H: Safety of hemihepatic vascular occlusion during resection of the liver. Surgery,
Gynecology & Obstetrics 164:155-158, 1987.
10. Makuuchi M, Hasegawa H, Yamazaki S, Takayasu K,
Moriyama N: The use of operative ultrasound as an
aid to liver resection in patients with hepatocellular
carcinoma. World Journal of Surgery 11:615-621,
1987.
11. Sakamoto M, Hirohashi S, Tsuda H, Ino Y,
Shimosato Y, Yamazaki S, Makuuchi M, Hasegawa
H, Terada M, Hosoda Y: Increasing incidence ofhepatocellular carcinoma possibly associated with
Non-A, Non-B hepatitis in Japan, disclosed by hepatitis B virus DNA analysis of surgically resected cases.
Cancer Research 48:7294-7297, 1989.
12. Makuuchi M, Takayama T, Gunven P, Kosuge T,
Yamazaki S, Hasegawa H: Restrictive versus liberal
blood transfusion policy for hepatectomies in cirrhotic patients. World Journal of Surgery 13:644-648,
1989.
13. Makuuchi M, Thai B.L, Takayasu K, Takayama T,
Kosuge T, Gunven P, Yamazaki S, Hasegawa H,
Ozaki H: Preoperative portal embolization to increasesafety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 107:521-527,
1990.
14. Takayama T, Makuuchi M, Hirohashi S, Sakamoto
M, Okazaki N, Takayasu K, Kosuge T, Motoo Y,
Yamazaki S, Hasegawa H: Malignant transformationof adenomatous hyperplasia to hepatocellular carcinoma. Lancet 33:1153-1155, 1990.
15. Kitahara S, Makuuchi M, Kawasaki S, Ishizone S,
Matsunami H, Kamada N, Kawarazaki H, Imanaka T:
Lyphoproliferative disorders after FK 506. Lancet
337:1234, 1991.
16. Kawasaki S, Makuuchi M, Ishizone S, Matsunami H,
Terada M, Kawarazaki H: Liver regeneration in recipients and donors after transplantation. Lancet
339:580-581, 1992.
17. Takayasu K, Wakao F, Moriyama N, Muramatsu Y,
Yamazaki S, Kosuge T, Takayama T, Okada S,
Okazaki N, Makuuchi M: Postresection recurrence ofhepatocellular carcinoma treated by arterial
embolization: Analysis of prognostic factors.
Hepatology 16:906-911, 1992.
18. Matsunami H, Makuuchi M, Kawasaki S, Ishizone S,
Mizusawa Y, Kawarazaki H, Takayama T: Livingrelated liver transplantation in fulminant hepatic failure. Lancet 340:1411-1412, 1992.
19. Makuuchi M, Kawasaki S, Noguchi T, Hashikura Y,
Matsunami H, Hayashi K, Harada H, Kakazu T,

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Takayama T, Kawarazaki H: Donor hepatectomy forliving related partial liver transplantation. Surgery
113:395-402, 1993.
20. Makuuchi M, Hashikura Y, Kawasaki S, Tan D,
Kosuge T, Takayama T: Personal experience of rightanterior segmentectomy (segments V and VIII. forhepatic malignancies. Surgery 114:52-581993.
21. Kawasaki S, Makuuchi M, Matsunami H, Hashikura
Y, Ikegami T, Chisuwa H, Ikeno T, Noike T,
Takayama T, Kawarazaki H: Preoperative measurement of segmental liver volume of donors for living
related liver transplantation. Hepatology 18:11151120, 1993.
22. Hashikura Y, Makuuchi M, Kawasaki S, Matsunami
H, Ikegami T, Nakazawa Y, Kiyosawa K, Ichida T:
Successful living-related partial liver transplantation
to an adult patient. Lancet 343:1233-1234, 1994.
23. Matsushita K, Kawasaki S, Makuuchi M: Arterial
ketone body ratio in liver surgery. Hepatology
20:331-335, 1994.
24. Hui A-M, Kawasaki S, Makuuchi M, Nakayama J,
Ikegami T, Miyagawa S: Liver injury following
normethermic ischemia in steatotic rat liver.
Hepatology 20:1287-1293, 1994.
25. Urata K, Kawasaki S, Matsunami H, Hashikura Y,
Ikegami T, Ishizone S, Momose Y, Komiyama A,
Makuuchi M: Calculation of child and adult standard
liver volume for liver transplantation. Hepatology
21:1317-1321, 1995.
26. Ichida T, Matsunami H, Kawasaki S, Makuuchi M,
Harada T, Itoh S, Asakura H: Living related-donorliver transplantation from adult to adult for primarybiliary cirrhosis. Annals of Internal Medicine
122:275-276, 1995.
27. Miyagawa S, Kawasaki S, Makuuchi M: Carcinoma
between hepatitis B and C viral infection : Tumor
multicentricity in cirrhotic liver with hepatic C.
Hepatology 24:307-310, 1996.
28. Nagai M, Kubota K, Kawasaki S, Takayama T, BandaiY, Makuuchi M: Are left-sided gallbladders reallylocated on the left side? Annals of Surgery 225:274280, 1997.
29. Kubota K, Makuuchi M, Kusaka K, Kobayashi T,
Miki K, Hasegawa K, Harihara Y, Takayama T:
Measurement of liver volume and hepatic functional
reserve as a guide to decision-making in resectional
surgery for hepatic tumors. Hepatology 26:11761181, 1997.
30. Kawasaki S, Makuuchi M, Matsunami H, Hashikura
Y, Ikegami T, Nakazawa Y, Chisuwa H, Terada M,
Miyagawa S: Living related liver transplantation in
adults. Annals of Surgery 227:269-274, 1998.
31. Abe H, Yamada N, Kamata K, Kumaki T, Shimada M,
Osuga J, Shionoiri F, Yahagi N, Kadowaki T,
Tamemoto H, Ishibashi S, Yazaki Y, Makuuchi M:
Hypertension, hypertriglyceridemia and impaired
endothelium-dependent vascular relaxation in micelacking insulin receptor substrate-1. Journal of
Clinical Investigation 101:1784-1788, 1998.

238

32. Takayama T, Makuuchi M, Hirohashi S, Sakamoto
M, Yamamoto J, Shimada K, Kosuge T, Okada S,
Takayasu K, Yamazaki S: Early hepatocellular carcinoma as an entity with a high rate of surgical cure.
Hepatology 28(5.
:1241-1246, 1998.
33. Takayama T, Sekine T, Kondo Y, Kakizoe T,
Makuuchi M: Adjuvant adoptive immunotherapy
against hepatocellular carcinoma. Hepatology
28:1436-1437, 1998.
34. Hui AM, Cui X, Makuuchi M, Li X, Shi YZ,
Takayama T: Decreased p27 (Kip1.
expression
and cyclin D1 overexpression, alone and in combination, influence recurrence and survival of patientswith resectable extrahepatic bile duct carcinoma.
Hepatology 30:1167-1173, 1999.
35. Tanaka S, Mori M, Sakamoto Y, Makuuchi M,
Sugimachi K, Wands JR: Biologic significance ofangiopoietion –2 expression in human hepatocellular
carcinoma. Journal of Clinical Investigation
1103:341-345, 1999.
36. Imamura H, Shimada R, Kubota M, Matsuyama Y,
Nakayama A, Miyagawa S, Makuuchi M, Kawasaki
S: Preoperative portal vein embolization : An audit of
84 patients. Hepatology 229:1099-1105, 1999.
37. Torzilli G, Minagawa M, Takayama T, Inoue K, Hui
AM, Kubota K, Ohtomo K, Makuuchi M: Accurate
preoperative evaluation of liver mass lesions withoutfine-needle biopsy. Hepatology 330:889-893, 1999.
38. Kosuge T, Yamamoto J, Shimada K, Yamasaki S,
Makuuchi M: Improved surgical results for hilar
cholangiocarcinoma with procedures including major
hepatic resection. Annals of Surgery 230:663-671,
1999.
39. Sugawara Y, Makuuchi M, Kato N, Shimotohno K,
Takada K: Enhancement of hepatitis C virus replication by Epstein-Barr virus-encoded nuclear antigen 1.
The EMBO (European Molecular Biology
Organization) Journal 18: 5755-5760, 1999.
40. Hui AM, Li X, Shi YZ, Torzilli G, Takayama T,
Makuuchi M p27(kip) Expression in normal epithelia, precancerous lesions, and carcinomas of thegallbladder: association with cancer progression a n dprognosis. Hepatology 31:1068-1072, 2000.
41. Kogure K, Kuwano H, Fujimaki N, Makuuchi M:
Relation among portal segmentation, proper hepaticvein, and external notch of the caudate lobe in thehuman liver. Annals of Surgery 231:223-228, 2000.
42. Minagawa M, Makuuchi M, Torzilli G, Takayama T,
Kawasaki S, Kosuge T, Yamamoto J, Imamura H:
Extension of the frontiers of surgical indications in
the treatment of liver metastases from colorectal cancer. Annals of Surgery 231:487-499, 2000.
43. Miki K, Al-Refaie W, Xu M, Jiang P, Tan Y, Bouret M,
Zhao M, Gupta A, Chishima T, Shimada H,
Makuuchi M, Moossa AR, Hoffman RM:
Methioninase gene therapy of human cancer cells is
synergistic with recombinant methioninase treatment. Cancer Research 60:2696-2702, 2000.
44. Takayama T, Sekine T, Makuuchi M, Yamasaki S,
Kosuge T, Yamamoto J, Shimada K, Sakamoto M,

Hirohashi S, Ohashi Y, Kakizoe T: Adoptive
immunotherapy to lower postsurgical recurrence
rates of hepatocellular carcinoma: a randomised trial.
The Lancet 356(9232. :802-807, 2000.
45. Arii S, Yamaoka Y, Futagawa S, Inoue K, Kobayashi
K, Kojiro M, Makuuchi M, Nakamura Y, Okita K,
Yamada R, For The Liver Cancer Study Group ofJapan: Results of surgical and nonsurgical treatment
for small-sized hepatocellular carcinomas : A
Retrospective and Nationwide Survery in Japan.
Hepatology 32:1224-1229, 2000.
46. Torzilli G, Makuuchi M, Midorikawa Y, Sano K,
Inoue K, Takayama T, Kubota K: Liver resection
without total vascular exclusion hazardous or beneficial? Annals of Surgery 233:167-175, 2001.
47. Minagawa M, Makuuchi M, Takayama T, Ohtomo K:
Selection criteria for hepatectomy in patients with
hepatocellular carcinoma and portal vein tumor
thrombus. Annals of Surgery 233:379-384, 2001.
48. Saiura A, Sato M, HirataY, Nagai R, Makuuchi M: letter to the editor: Cirulating smooth muscle progenitor cells contribute to atherosclerosis. Nature
Medicine 7(4): 382-383, 2001.
49. Kubota K, Takayama T, Sano K, Hasegawa K, Aoki T,
Sugawara Y, Makuuchi M: Small bile duct reconstruction of the caudate lobe in living-related livertransplantation. Annals of Surgery 235(2):174-177,
2002.
50. Sano K, Makuuchi M, Miki K, Maema A, Sugawara
Y, Imamura H, Matsunami H, Takayama T:
Evaluation of hepatic venous congestion proposed
indication criteria for hepatic vein reconstruction.
Annals of Surgery 236:241-247, 2002.

239

Department of Urology
Outline and Research Objectives
Originally, our department had been attached to Department of Dermatology since 1890,
later in 1926, the current department of urology was founded. Initially, urology dealt withurinary tract infection, especially gonorrheal urethritis. Subsequently, its scope has been
expanded dramatically and now is covering the diseases of the adrenal gland, the kidney,
the urinary tract and the male genital system by means of surgical and non-surgical procedures. Its subspecialty includes pediatric urology, neurourology, female urology, renal transplantation, vascular surgery, endocrine surgery and geriatric urology. For this reason, urology in these days is beyond a section of surgery.
During these progresses, we have been taking national and international leadership indeveloping and applying the new or minimally invasive treatment modalities. They are
exemplified by endoscopic management of the diseases in the upper urinary tract, extracorporeal shock wave lithotripsy (ESWL), laser therapies for prostatic hypertrophy and laparoscopic adrenalectomy or nephrectomy substituting open procedures. Nowadays we are
expanding the frontier by introducing less invasive surgeries or more sophisticated treatment modalities to urology. This expansion is supported by incorporating updated cellularand molecular biology to clinical medicine.

Faculties and Students
Professor and Chair

Tadaichi Kitamura, M. D., Ph. D.
(1998-)
Associate Professors Yukio Homma, M. D., Ph. D.,
Nobutaka Ohta, M. D., Ph. D.
Lecturers
Takumi Takeuchi, M. D., Ph. D.,
Satoru Takahashi, M. D., Ph. D.
Kyoichi Tomita, M. D., Ph. D.,
Makoto Suzuki, M. D., Ph. D.
Associate ...............................12
Graduate student ..................11
Research student.....................3
Secretary .................................5

Past Research and Major Accomplishments
1) Clinical accomplishment
We have been applying endoscopic procedures toclinical practice as less invasive treatment modalities.
For example, we are the pioneers of pyeolureteroscopy, by which the upper urinary tract diseases are endoscopically managed.
We have developed new prognostic predictors
such as fluorescence in-situ hybridization analysis of
exfoliated urothelial cells for bladder cancer recurrence. We examined accuracy of diagnostic procedures for voiding dysfunctions and detected anatomical and electrophysiological abnormalities of the striated urethral sphincter in stress urinary incontinent

240

women.
As the new treatment modalities, dendritic cell
immunotherapy was successfully performed inpatients with metastatic renal cell carcinoma.
Magnetic stimulation of the sacral roots was developed to improve urinary incontinence.
2) Basic research
In oncology field, we found that hepatocyte
growth factor, IL4, Fas ligand or caspase-1 enhanced
the invasiveness of renal cell carcinoma, and that antiapoptotic Bcl-2 proto-oncogene expression increased
resistance of human prostatic cancer cells to various
apoptotic stimuli. For bladder cancer we detected frequent agreement of genetic alternations (loss of heterozygosity at 10 microsatellite loci and methylationof p16INK4 CpG-island) in cancerous mucosa and “normal” bladder mucosa, suggesting morphologically normal epithelium possesses genetic or epigenetic aberrations common with cancer.
In nephrology we produced a knockout mousemodel of autosomal dominant polycystic kidney disease (ADPKD) with a targeted deletion of Pkd1 .
Homozygote embryos developed hydrops, cardiac
conotruncal defects and renal cystogenesis partly
through the E-cadherin-b-catenin-c–MYC pathway
and tyrosine phosphorylation of EGFR and Gab1.
Maternally-administered pioglitazone, a thiazolidinedione compound, improved survival of knockout
embryos, the degree of renal cystogenesis andendothelial dysfunction, suggesting thiazolidine-diones as a new therapeutic for ADPKD.
Other basic investigations include transplantation
research to improve graft survival by expressing IL4
or Fas ligand in the graft, and pharmacologic researches to examine adrenoceptor expression in the prostateor to apply adrenomedullin, a vasorelaxant peptide, toerectile dysfunction and nephron sparing surgery.
3) Investigation in urinary virology
Over these 15 years, we have been investigating
the mode of infection in urinary polyomavirus JC
virus (JCV) that causes progressive multifocal leukoencephalopathy in immuno-compromized patients. It
has long been known since 1970’s that JCV is ubiquitous in the human population and infects children
asymptomatically. However, other characteristics of
JCV had not been elucidated further. From our longrun study for about 15 years, many facts have been
elucidated. JCV persists and replicates in renal tissue
throughout life and is shed frequently into urine afterlate adolescent and the excretion rate exceeds 60%
after around age 50.
The main mode of transmission of JCV is fromparents to children through long term cohabitation.
During the course of study, we have identified 3
major types of JCV, types A, B and C, according totheir DNA sequence variance. A distinct relationshipwas demonstrated between JCV genotypes andhuman races. Type A is predominant in Caucasianand type B predominates in Asian, while mostAfricans have type C, which is verified by phylogenetic tree analysis. Recently Japanese-Americans haveshown to reserve their original or Japanese type of JC
virus, which supports the hypothesis that JCV istransmitted mostly within the family through longterm cohabitation. As of the end of September in
2002, many urine samples have been collected fromacross the world more than 50 different countries. In
a result, JCV can be classified into at least 12 JCV
genotypes that occupy unique domains in the world.
Each of 12 JCV genotypes has a special association
with distinct human population. Those results havebeen published in 20 papers of PNAS, J of Virology,
Virology, J of Infectious Diseases, and so on.

Current Research
We are more and more concentrating on prostatecancer as the target disease. The expression level of
estrogen receptor and its responsive genes are analyzed to further understand molecular mechanisms of
responsiveness of prostate cancer cells to estrogens.
The expression level of these molecules in humanspecimens is investigated for predictability of clinicalprogression of the prostate cancer. Cadherin and its
variant forms are also investigated for its predictabili-

ty of invasion and metastasis of the prostate cancer,
urinary bladder cancer and renal pelvic cancer.
Genetic variant of metabolic activation of estramustine phosphate is analyzed for individual patientswith hormone refractory prostate cancer to minimize
adverse events associated with the agent.
Laparoscopic surgery has been established for adrenalectomy, and now being used for prostatectomy,
nephrectomy and nephroureterectomy. Treatment foradvanced cancer is a challenge in oncology. A new
combination chemotherapy regime including paclitaxel and cis-platinum is attempted for metastatic
prostate and bladder cancers. Tissue oxidative stress,
which is measured by the ratio of reduced-to-total coenzyme Q contents, is now investigated in relation tocarcinogenesis, invasion and metastasis of prostatecancer in rats.
Apart form prostate cancer we are developing
instruments to measure symptoms and quality of life
to assess the efficacy of treatment for voiding dysfunction. As an innovative treatment modality for
benign prostatic hyperplasia, high-intensity-focusedultrasound that evaporates prostatic tissue is being
applied to reduce the urethral obstruction. Alphaadrenoceptor is known to mediate tonus of bladderoutlet. Knock out mice of the receptors are being
investigated for their voiding habits and physiologicalcharacteristics of the prostate and bladder. We are
exploring genetic abnormality in recurrent stone formers with special interest in genes related to sodium
dicarboxylate cotransporter, which transports citrate
in renal tubules. For virology we are now examining
the offspring of mixed marriages to address the issueof whether JCV has a paternal or maternal bias to its
transmission to children. JC virus genotypes in AINU
people and Antarctic people are analyzed to obtainfurther information on migration of human-beings in
the history..

Future Prospect
Of clinical relevance, improving skills for endoscopic surgeries, especially for laparoscopic procedures
are mandatory.
In the field of basic research, tailor-made medicine
for advanced prostate cancer will be mainly pursued
hereafter, as well as elucidating the pathogenesis ofurological malignancies. Besides oncology, clinical andbasic research will be performed in the fields of neurogenic bladder, female urology, geriatric urology,
urolithiasis, erectile dysfunction and urinary virology.

Research Grants
1. Grant source Grant-in-Aid for Scientific Research (A)from the Ministry of Education, Science, Sports and

241

2.

3.

4.

5.

Culture, Japan Research title Application of genetherapy in urologic oncology Principle investigator
Tadaichi Kitamura Fund amount 28,800,000 Yen
Term 1999-2002
Grant source Grant-in-Aid for Scientific Research (C)from the Ministry of Education, Science, Sports andCulture, Japan Research title Prevention of prostate
carcinogenesis by suppressing tissue oxidative stressPrinciple investigator Yukio Homma Fund amount
3,200,000 Yen Term 2001-2004
Grant source Grant-in-Aid for Scientific Research (B)from the Ministry of Education, Science, Sports andCulture, Japan Research title Functional role ofadrenoceptor subtype in lower urinary tract obstruction in knockout mice Principle investigator
Nobutaka Ohta Fund amount 14,700,000 Yen Term
2001-2002
Grant source Grant-in-Aid for Scientific Research (C)from the Ministry of Education, Science, Sports andCulture, Japan Research title Estrogen receptors andestrogen receptor responsive genes in prostate cancer
and benign hyperplasia Principle investigator Satoru
Takahashi Fund amount 4,000,000 Yen Term 20022003
Grant source Grant-in-Aid for Scientific Research (C)from the Ministry of Education, Science, Sports andCulture, Japan Research title Role of cadherins ininvasion and metastasis of prostate cancer Principle
investigator Kyoichi Tomita Fund amount 3,600,000
Yen Term 2001-2002

Select Publications
1. Guo J, Sugimoto C, Kitamura T, Ebihara H, Kato A,
Guo Z, Liu J, Zheng SP, Wang YL, Na YQ, Suzuki M,
Taguchi F and Yogo Y. Four geographically distinct
genotypes of JC virus are prevalent in China andMongolia: implications for the racial composition ofmodern China. J. Gen. Virol. 79, 2499-2505, 1998.
2. Hara K, Sugimoto C, Kitamura T, Aoki N, Taguchi F
and Yogo Y. Archetype JC virus efficiently replicatesin COS-7 Cells, simian cells constitutively expressing
simian virus 40 T antigen. J. Virol. 72, 5335-5342,
1998.
3. Homma Y, Gotoh M, Takei M, Kawabe K and
Yamaguchi T. Predictability of conventional tests for
bladder outlet obstruction assessment in benign prostatic hyperplasia. Int. J. Urol. 5, 61-66, 1998.
4. Homma Y, Kawabe K and Hayashi K. Urological morbidity and its influence on global satisfaction withtreatment outocome after radical prostatectomy forprostate cancer. Int. J. Urol. 5, 556-561, 1998.
5. Kitamura T, Sugimoto C, Ebihara H, Kato A, Guo J,
Taguchi F, Tominaga T, Ogawa Y, Ohta N, Kizu N,
Imamura K, Funaki H, Kurosawa T, Ichikawa S,
Suzuki T, Chiba K, Nagashima K, Yasumoto S andYogo Y. Peopling of Japan as revealed by genotypingof urinary JC virus DNA. Anthropol. Sci. 4,311-325,
1998.

242

6. Aoki N, Kitamura T, Tominaga, T, Fukumori N,
Sakamoto Y, Kato K and Mori M.
Immunohistochemical detection of JC virus in
Nontumorous renal tissue of a patient with renal
cancer but without progressive multifocal leukoencephalopathy. J. Clin. Microbiol. 37,1165-1167, 1999.
7. Homma Y, Akaza H, Okada K, Yokoyama M,
Moriyama N, Usami M, Hirao Y, Tsushima T,
Sakamoto A, Ohashi Y, Aso Y and Prostate Cancer
Study Group. Early results of radical prostatectomy
and adjuvant endocrine therapy for prostate cancer
with or without preoperative androgen deprivation.
Int. J. Urol. 6, 229-237,1999.
8. Horie S, Aruga S, Kawamata H, Okui N, Kakizoe T
and Kitamura T. Biological role of HGF/MET pathway in renal cell carcinoma. J. Urol. 161, 990-997,
1999.
9. Kajiwara T, TakeuchiI T, Ueki T, Moriyama N, Ueki
K, Kakizoe T and Kawabe K. Effect of Bcl-2 overexpression in human prostate cancer cells in vitro andin vivo. Int. J. Urol. 6, 520-525, 1999.
10. Nishimatsu H, Takeuchi T, Ueki T, Kajiwara T,
Moriyama N, Ishida T, Li B, Kakizoe T and Kitamura
T. Fas ligand expression enhances growth of murine
renal cell carcinoma in vivo. Cancer Immunol.
Immunother. 48, 56-61, 1999.
11. Nishimatsu H, Moriyama N, Hamada K, Ukai Y,
Yamazaki S, Kameyama S, Konno N, Ishida Y, Ishii
Y, Murayama T and Kitamura T. Contractile responses to alpha1- adrenoceptor agonists in isolated
human male and female urethra. BJU Int. 84, 515520, 1999.
12. Suzuki M, Hosaka Y, Matsushima H, Goto T,
Kitamura T and Kawabe K. Butyro- lactone I induced
cyclin B1, G2/M arrest, and skipping of mitosis in
human prostatic cell Lines. Cancer Lett. 57, 121-130,
1999.
13. Takeuchi T, Ueki T, Nishimatsu H, Kajiwara T,
Ishida T, Jishage K, Ueda O, Suzuki H, Li B,
Moriyama N and Kitamura T. Accelerated rejectionof Fas-ligand expressing heart grafts. J. Immunol.
162, 518-522, 1999.
14. Aruga S, Wehrli S, Kaissling B, Moe O W, Preisig P A,
Pajor A M, and Alpern R J. Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance
in rat kidney. Kidney Int. 58, 206-215, 2000.
15. Fujishiro T, Enomoto H, Ugawa Y, Takahashi S,
Ueno S and Kitamura T. Magnetic stimulation of thesacral roots in the treatment of stress incontinence:an investigational study and a placebo controlled
trial. J.Urol. 164, 1277-1279, 2000.
16. Homma Y, Yamaguchi O, Kageyama S, Nishizawa O,
Yoshida M and Kawabe K. Nocturia in the adult:
Classification on the basis of the largest voided volume and nocturnal urine production. J.Urol. 163,
777-781, 2000.
17. Homma Y, Hamade K, Nakayama Y, Tsujimoto G
and Kawabe K. Effects of castration on contraction
and alfa1-adrenoceptor expression in rat prostate.
Brit. J. Pharmacol. 131, 1454-1460, 2000.

18. Homma Y, Kondo Y, Takahashi S, Kitamura T and
Kawabe K. Reproducibility of cystometry in overactive detrusor. Eur. Urol. 38, 681-685, 2000.
19. Kato A, Sugimoto C, Zheng HY, Kitamura T and Yogo
Y. Lack of disease-specific amino acid changes in theviral proteins of JC virus isolates from the brain with
progressive multifocal leukoencephalopathy. Arch.
Virol. 145, 2173-2182, 2000.
20. Kume H, Oda H, Nakatsuru Y, Shimizu Y, Tkahashi
Y, Matsumoto T, Inoue S, Kameyama S, Kitamura T
and Ishikawa T. Genetic idenitification of bilateral
primary or metastatic nonpapillary renal cell carcinoma. BJU Int. 86, 208-212, 2000.
21. Muto S, Horie S, Takahashi S, Tomita K and
Kitamura T. Genetic and epigenetic alteration in normal bladder epithelium in patients with metachronous bladder cancer. Cancer Res. 60, 4021-4025,
2000.
22. Takahashi S, Homma Y, Fujishiro T, Hosaka Y,
Kitamura T and Kawabe K. Electromyographic studyof the striated urethral sphincter in type 3 stressincontinence: evidence of myogenic-dominant damages. Urology 56, 946-950, 2000.
23. Takeuchi T, Nishimatsu H, Ueki T, Kajiwara T,
Fukuhara H, Ishida T, Moriyama N and Kitamura T.
Differentially expressed mRNAs in androgen-independent but not androgen-dependent Shionogi carcinoma. Urol. Res. 28, 82-85, 2000.
24. Tomita K, van Bokhoven A, van Leenders GJ, Ruijter
ET, Jansen CF, Bussemakers MJ, Schalken JA.
Cadherin switching in human prostate cancer progression. Cancer Res. 60, 3650-3654, 2000
25. Tomita K, van Bokhoven A, Jansen CF, Bussemakers
MJ and Schalken JA. Coordinate recruitment of Ecadherin and ALCAM to cell-cell contacts by alphacatenin. Biochem Biophys. Res. Commun. 267, 870874, 2000.
26. Akiyama H, Kurosu T, Sakashita C, Inoue T, Mori S,
Ohashi K, Tanikawa S, Sakamaki H, Onozawa Y,
Chen Q, Zheng H and Kitamura K. Adenovirus is a
key pathogen in hemorrhagic cystitis associated withbone marrow transplantation. Clin. Infect. Dis. 32,
1325-1330, 2001.
27. Fukuhara H, Maruyama T, Nomura S, Oshimura M,
Kitamura T, Sekiya T and Murakami Y. Functional
evidence for the presence of tumor suppressor geneon chromosome 10p15 in human prostate cancers.
Oncogene 20, 314-319, 2001.
28. Fujimura T, Takahashi S, Urano T, Ogawa S, Ouchi
Y, Kitamura T, Muramatsu M and Inoue S.
Differential expression of estrogen receptor beta
(ERbeta) and its C-terminal truncated splice variant
ER betacx as prognostic predictors in human prostatic cancer. Biochem. Biophys. Res. Commun. 289, 692695, 2001.
29. Guo Z, Zheng SP, Sugimoto C, Wang YL, Zheng HY,
Takasaka T, Kitamura T, Guo J and Yogo Y. JC virus
genotypes in Northwestern China: Implications for
its population history. Anthropol. Sci. 3, 203-212,
2001.

30. Ishiwata S, Takahashi S, Homma Y, Tanaka Y,
Kameyama S, Hosaka Y and Kitamura T.
Noninvasive detection and prediction of bladder cancer by fluorescence in situ hybridization analysis of
exfoliated urothelial cells in voided urine. Urology
57, 811-815, 2001.
31. Kamijo T, Sato T, Nagatomi Y and Kitamura T.
Induction of apoptosis by cyclooxygenase-2
inhibitors in prostate cancer cell lines. Int. J. Urol. 8,35-39, 2001.
32. Kanda H, Kubo K, Hamasaki K, Kanda Y, Nakao A,
Kitamura T, Fujita T, Yamamoto K and Mimura T.
Influence of various hemodialysis membranes on theplasma (1-3)-beta-D-glucan level. Kidney Int. 60, 319323, 2001.
33. Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T,
Maruyama T, Ghosh Hara P, Pletcher M, Isomura M,
Onizuka M, Kitamura T, Sekiya T, Reeves RH and
Murakami Y. TSLC1 is tumor-suppressor gene inhuman non-small-cell lung cancer. Nature Genetics
27, 427-430, 2001.
34. Kondo Y, Homma Y, Takahashi S, Kitamura T and
Kawabe K. Transvaginal ultrasonography of urethral
sphincter in continent and incontinent women. J.
Urol. 165, 149-152, 2001.
35. Nishimatsu H, Suzuki E, Nagata D, Moriyama N,
Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo
H, Goto A, Kitamura T and Hirata Y.
Adrenomedullin induces endothelium- dependentvasorelaxation via the phosphatidylinositol 3kinase/akt-dependent pathway in rat aorta. Circul.
Res. 89, 63-70, 2001.
36. Nishimatsu H, Hirata Y, Hayakawa H, Nagata D,
Satonaka H, Suzuki E, Horie S, Takeuchi T, Ohta N,
Homma Y, Minowada S, Nagai R, Kawabe K and
Kitamura T. Effects of intracavernous administrationof adrenomedullin on erectile function in rats.
Peptides 22, 1913- 1918, 2001.
37. Ueki T, Takeuchi T, Nishimatsu H, Kajiwara T,
Moriyama N, Narita Y, Ueki K and Kitamura T.
Silencing of caspase-1 gene occurs in murine andhuman renal cancer cells and confers solid tumor
growth in vivo. Int. J. Cancer 91, 673-679, 2001.
38. Yanai Y, Horie S, Yamamoto K, Yamauchi H, Ikegami
H, Kurimoto M and Kitamura T. Characterization of
the anti-tumor activities of IFN-alfa8 in renal cell carcinoma cells. J. Interferon Cytokine Res. 21, 11291136, 2001.
39. Azuma T, Horie S, Tomita K, Takahashi T, Tanaka Y,
Kashiwase K, Nieda M, Takeuchi T, Ohta N, Shibata
Y, Hirai H and Kitamura T. Dendritic cell
immunotherapy for patients with metastatic renal
cell carcinoma: University of Tokyo experience. Int.
J. Urol. 9, 340-346, 2002.
40. Fujishiro T, Takahashi S, Enomoto H, Ugawa Y,
Ueno S and Kitamura T. Magnetic stimulation of thesacral roots in the treatment of urinary frequency
and urge incontinence: an investigational study anda placebo controlled trial. J. Urol. 168, 1036-1039,
2002.

243

41. Homma Y, Yamaguchi T, Kondo Y, Horie S,
Takahashi S and Kitamura T. Significance of nocturia
in the international prostate symptom score forbenign prostatic hyperplasia. J. Urol. 167, 172-176,
2002.
42. Homma Y, Ando T, Yoshida M, Kageyama S, Takei
M, Kimoto K, Ishizuka O, Gotoh M and Hashimoto
T. Voiding and incontinence frequencies - variabilityof diary data and required diary length. Neurourol.
Urodynam. 21, 204-209, 2002.
43. Kitamura T, Nishimatsu H, Hamamoto T, Tomita K,
Takeuchi T and Ohta N. EMP combination
chemotherapy and low-dose monotherapy inadvanced prostate cancer. Expert Rev. Anticancer
Ther. 2, 59-71, 2002.
44. Matsushima H, Kawabe K, Fujime M, Kitamura T,
Homma Y, Kishi H, Kawamura T, Umeda, T, Ohishi,Y, Murai M, Kawai T, Yoshida H and Fukuda T.
Treatment of patients with superficial bladder cancer
by intravesical instillation of anticancer drugs plus
oral chemotherapy following TUR- Bt: A randomized
controlled trial. Oncol. Rep. 9, 283-288, 2002.
45. Muto S, Aiba A, Saito Y, Nakao K, Nakamura K,
Tomita K, Kitamura T, Kurabayashi M, Nagai R,
Higashihara E, Harris PC, Katsuki M and Horie S.
Pioglitazone improves the phenotype and molecular
defects of a targeted Pkd1 mutant. Hum. Mol. Genet.
15, 1731- 1742, 2002.
46. Nishimatsu H, Hirata Y, Shindo T, Kurihara H,
Kakoki M, Nagata D, Hayakawa H, Satonaka H, Sata
M, Tojo A, Suzuki E, Kangawa K, Matsuo H,
Kitamura T and Nagai R. Role of endogenous
adrenomedullin in the regulation of vascular tone
and ischemic renal injury: studies ontransgenic/knockout mice of adrenomedullin gene.
Circul. Res. 90, 657-663, 2002.
47. Saruwatari L, Sugimoto C, Kitamura T, Ohno N,
Sakai E, Shresta P, Hoa BK, Phi PTP, An HPH, Tuyet
NTA, Honjo T, Kobayashi N, Zheng HY, Takasaka T
and Yogo Y. Asian domains of four major genotypesof JC virus, Af2, B1-b, CY and SC. Arch. Virol. 147, 110, 2002.
48. Sugimoto C, Hasegawa, M, Kato A, Zheng HY,
Ebihara H, Taguchi F, Kitamura T, Yogo Y. Evolutionof human polyomavirus JC: Implications for the population history of humans. J.Mol.Evol. 54, 285-297,
2002.
49. Suzuki M, Zheng H-Y, Takasaka T, Sugimoto C,
Kitamura T, Beutler E and Yogo Y. Asian genotypesof JC virus in Japanese-Americans suggests familialtransmission. J. Virol. 2002, in press.
50. Nishimatsu H, Hirata Y, Shindo T, Kurihara H,
Suzuki E, Sata M, Satonaka H, Tanaka R, Nagata D,
Kakoki M, Hayakawa H and Nagai R. Epitherial
responses of the aorta from adrenomedullin transgenic mice and knocckout mice. Hypertens. Res.
2002, in press.

244

Department ofSurgical Oncology
Outline and Research Objectives
The Department of Surgical Oncology was taken over from the First Department ofSurgery, which was established in 1893. Dr. Tetsuichiro Muto, who was the ninth Professorof the First Department of Surgery, was appointed as the first Professor of the Departmentof Surgical Oncology in 1997 based on the introduction of a new system for postgraduate
education. Dr. Hirokazu Nagawa was appointed as the second Professor of this department
in 1999.
The main research objective in this department is to augment quality of life in patientswith malignant disorders by applying knowledge of radiology, molecular biology, cell biology and immunology to clinical setting as well as surgical techniques.
The Department of Surgical Oncology provides comprehensive evaluation, diagnosis,
treatment and management for adult patients with both general and oncologic surgicalproblems, in the ambulatory as well as inpatient setting. Additionally, surgical specialities inthe department include the treatment of benign and malignant disorders of the breast andmanagement of malignancies of the gastrointestinal tract (esophageal, gastric, and colorectal). The department is also well known for its innovative therapy for inflammatory bowel
disease. Department specialists have expertise in biological cancer immunotherapy,
chemotherapy for a variety of malignancies, and radiotherapy for rectal cancer. The department was responsible for 309 inpatients and 18,845 outpatients in the 2000 fiscal year, and402 inpatients and 16,663 outpatients in the 2001 fiscal year.

Faculties and Students
Professor and Chair

Hirokazu NAGAWA, M.D., Ph.D.
(1999-)
Associate Professors Toshiaki WATANABE, M.D., Ph.D.
Lecturer
Joji KITAYAMA, M.D., Ph.D.
Associate .................................9
Postdoctoral Fellow ................5
Graduate Students ................16
Research Students...................7
Secretaries ...............................5

Past Research and Major Accomplishments
1. Preoperative radiotherapy for lower rectal cancer
Preoperative radiation therapy for advanced rectal
cancer has been reported to reduce local recurrence instudies in Western countries, but its effectiveness has
not yet found wide acceptance in Japan. The reason
for this seems to be that although the local recurrence
rate is lower in the irradiated group than that in the
non-irradiated group in studies in Western countries,
the rate shows values around 10% (7.8% to 12.4 %),which is almost equal to or somewhat higher than therate after surgical treatment alone in Japan. Thismight be due to the difference between Westerncountries and Japan in terms of surgical procedure inthat the importance of regional lymphadenectomy
including lateral node dissection has been emphasized
for advanced lower rectal cancer in Japan. Thus,
extended lymphadenectomy including lateral nodedissection (EXT-L) contributes to a low incidence of
local recurrence of lower rectal cancer. However, EXTL is frequently associated with impairment of sexual
and urinary functions. We therefore compared theeffectiveness of preoperative radiotherapy with thatof EXT-L in a prospective, randomized, controlled
study as well as a retrospective analysis. Our studies
have suggested that lateral node dissection is not necessary in terms of curability for patients withadvanced carcinoma of the lower rectum who undergo preoperative radiotherapy (reprint numbers 1 and
2).
Thus, preoperative radiotherapy reduces the rateof local recurrence and improves the chance of survival in patients with resectable, advanced rectal carcinoma. However, because not all tumors respond similarly to radiation, sorting out suitable patients isrequired to irradiate tumors rationally. Therefore, weinvestigated the predicting values of radiosensitivity
in human rectal carcinoma. Specifically, p53,
p21/WAF1 and Ku protein expressions in preradiation245

biopsy specimens from patients with primary rectal
carcinoma were analyzed immunohistochemically.
The proteins of p53 and p21 are those related to cell
cycle and apoptosis pathways, and Ku protein is related to the repair of damaged DNA. Our studies haveindicated that immunohistochemistry detection of
p53, p21 and Ku expressions may be useful parameters for selecting patients with rectal carcinoma forpreoperative radiotherapy (reprint numbers 3 and 4).
2. Appropriate application of chemotherapy topatients with colon carcinoma
A combined administration of 5-fluorouracil (5-FU)
and leucovorin is regarded as a standard chemotherapy for patients with colon carcinoma. Not all tumors,
however, respond similarly to the regimen of
chemotherapy. Therefore, we investigated the predicting values of chemosensitivity in patients with colon
carcinoma from viewpoints of metabolism and apoptotic effects of 5-FU on the tumors. Specifically, weinvestigated the effects of thymidylate synthase (TS)and dihydropyrimidine dehydrogenase (DPD) frommetabolic aspects and Bcl-2 family from apoptotic
aspects on the colon carcinoma. Our studies haveindicated that TS is a prognostic factor for colon carcinoma, and that 5-FU adjuvant chemotherapy is appropriate for colon carcinoma with high expression of TS
and low expression of DPD (reprint number 5). Ourstudies have also suggested that the ratio of Bcl-XL(apoptosis inhibitor) to Bax (apoptosis inducer) is
related to chemosensitivity to 5-FU (reprint number
6).
3. Analysis of cell functions from the viewpoint ofanti-tumor immunity
Immunotherapy using dendritic cells (DCs) is amodality for cancer patients. We have analyzed characteristics of DCs for the purpose of applying effective
DCs to clinical setting. We have demonstrated for the
first time the direct activation of human natural killer(NK) cells by DC-NK cell interaction in vitro, suggesting that DCs may have a central role linking the
innate and adaptive immune responses. Moreover, instimulating NK cell function, peripheral blood DCs
appear to have a different potential from monocytederived DCs. Furthermore, the function of dendritic
cells (DCs), antigen-presenting cells that can initiate
and regulate cellular and humoral responses, is highly
influenced by their level of maturation. Immature DCs
may be harmful in anti-tumor immunotherapy,
because they can induce immunotolerance rather thanimmunostimulation. With respect to this issue, wehave demonstrated that DC culture in an anti-CD40
monoclonal antibody-immobilized plate in medium
supplemented with interferon-gamma has a positive
impact on DC maturation and may be optimal for elic-246

iting an antigen-specific T-cell response without theneed for CD4+ T-helper epitopes (reprint number 7).
Another candidate of effector cells on the antitumor immunity is a subset of natural killer (NK) cells
in the liver, which are enhanced by alpha-glycosylceramides. Alpha-glycosylceramides induce antitumor
immunity in various murine cancer models. Our
observations have strongly suggested the potential
usefulness of alpha-glycosylceramides for
immunotherapy of liver cancer in humans based on
their ability to activate CD3-CD56+ NK cells in theliver (reprint number 8).
4. Experimental analysis of hematogenous andlymphatic metastasis on gastrointestinal cancers
We have made efforts to elucidate the mechanismof hematogenous and lymphatic metastasis on gastrointestinal cancers using a flow adhesion system.
With respect to hematogenous metastasis, cultured
colon cancer cells bound to laminin (LM), but not to
fibronectin or vitronectin under the physiologicalshear condition. Most of the tethered cells did notroll, but arrested immediately and spread within 1030 min on LM under the continuous presence of shear
flow. Our data have suggested that LM can mediatefrom tethering to spreading of colon cancer cells
under the blood flow and plays an essential role inhematogenous metastasis. Our studies have also suggested that E-selectin alone can mediate colon cancer
cell lodgment and subsequent metastasis without thecontribution of integrin molecules and that the different distribution of E-selectin ligands may affect theadhesion behavior of colon cancer cells in flow conditions (reprint number 9).
With respect to lymphatic metastasis, our studies
have indicated high affinity between cancer cells andlymphatic endothelial cells (LEC), and suggested thatlymph node metastasis arises from cancer cells adherent to LEC, which can be augmented by an inflammatory stimulus.
5. Projects on upper gastrointestinal tract
Although our study is mainly focused on colorectal
cancer, we have also investigated and achieved gastricand esophageal cancers in terms of scientific research
as well as surgical techniques. Recently, we identified
X-chromosome-linked inhibitor of apoptosis protein(XIAP) and the gene was designated as hRFI, standingfor human Ring Finger homologous to IAP type.
Northern blot analysis showed that in 70% (14 out of20) of esophageal cancer patients, expression of hRFI
in cancerous regions was two or more times higher
than in the corresponding normal tissues (reprint
number 10). The other major accomplishment in thisfield is listed as follows.

1. p21 Waf1/Cip1 expression is a prognostic marker
in curatively resected esophageal squamous cell
carcinoma, but not p27Kip1, p53, or Rb
2. Local resection with lymphadenectomy for earlygastric cancer
3. Quantative analysis of the cyclin expression inhuman esophageal cancer cell lines
4. Extended lymph node dissection for gastric cancer
cases with N2 lymph node metastasis
5. Microvascular anastomosis for additional bloodflow in reconstruction after intrathoracic
esophageal carcinoma surgery
6. Prognostic significance of non-gastric malignancy
after treatment of early gastric cancer
The relationship of macroscopic shape of superficial esophageal carcinoma to depth of invasion andregional lymph node metastasis.

Current Research
The clinical and academic interests of our department are the upper and lower gastrointestinal tract.
We have begun to apply the techniques used inmolecular and cellular biology to our research basedon the past research and major accomplishment mentioned above. The following are the major themes
under research.
1. Cancer therapy targeting to the tumor vessels
2. Immunotherapy with dendritic cells
3. Modulated chemotherapy in association with genetherapy
4. Genetic analysis of colorectal cancer and adenoma
5. Carcinogenesis in superficial early colorectal cancer
6. Prognostic factor of early colorectal cancer
7. Genetic alterations in synchronous and metachronous multiple colorectal cancers
8. Microsatellite instability and a risk of developing
multiple colorectal cancers
9. Surveillance program following colectomy for colorectal cancer
10. The mechanism of liver metastasis of colorectal
cancer
11. Genetic alterations in ulcerative colitis
12. Association study of candidate genes in ulcerative
colitis13. Carcinogenesis in ulcerative colitis
14. Cancer surveillance in ulcerative colitis
15. Association study of candidate genes in Crohn’sdisease
16. Angiogenesis inhibition in peritoneal metastasis ofgastric cancer

Future Prospects
Research projects described in the past researchand the current research are continuously pursued inour department. More specifically, we are interested
in cancer therapy targeting angiogenesis resulting
from tumor development, immunotherapy with dendritic cells and effective chemotherapy for patientswith cancer. We are also interested in investigating
what mechanism is involved in metastasis, and how
the metastasis is inhibited or suppressed in cancer
patients.
It is considered that the need for appropriate clinical and psychological care for outpatients is increasing
due to the rising number of patients with intractable
malignant diseases. The number of major operations
for elderly patients is also increasing. Taking all thesetrends into account, we need to make greater endeavors in our clinical practice and research in order tomeet the demands of today’s society.

Research Grant
1. Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science andTechnology of Japan, 1997-2001, ¥112,800, 000
2. Grant-in-Aid for Scientific Research from the
Ministry of Health, Labor and Welfare of Japan,
1997-2001, ¥45,500,000
3. Grant-in-Aid for Scientific Research from the
Ministry of Public Management, Home Affairs, Posts
and Telecommunications of Japan, 1997-2001,¥140,600,000

Select Publications (50 papers)
Colorectum
1. Komuro Y, Watanabe T, Hosoi Y, Matsumoto Y,
Nakagawa K, Tsuno N, Kazama S, Kitayama J, Suzuki
N, Nagawa H. The expression pattern of Ku correlates with tumor radiosensitivity and disease freesurvival in patients with rectal carcinoma. Cancer 95,
1199-1205, 2002.
2. Watanabe T, Tsurita G, Muto T, Sawada T, Sunouchi
K, Higuchi Y, Komuro Y, Kanazawa T, Iijima T,
Miyaki M, Nagawa H. Extended lymphadenectomy
and preoperative radiotherapy for lower rectal cancers. Surgery 132, 27-33, 2002.
3. Nagawa H, Muto T, Sunouchi K, Higuchi Y, Tsurita
G, Watanabe T, Sawada T. Randomized, controlled
trial of lateral node dissection vs. nerve-preserving
resection in patients with rectal cancer after preoperative radiotherapy. Dis Colon Rectum 44, 1274-1280,
2001.
4. Kyo K, Muto T, Nagawa H, Lathrop GM, Nakamura
Y. Association of distinct variants of the intestinal247

mucin gene MUC3A with ulcerative colitis andCrohn’s disease. J Hum Genet 46, 5-20, 2001.
5. Masaki T, Sugiyama M, Atomi Y, Matsuoka H, Abe
N, Watanabe T, Nagawa H, Muto T. The indicationof local excision for T2 rectal carcinomas. Am J Surg
181, 133-7, 2001.
6. Shinozaki M, Watanabe T, Kubota Y, Sawada T,
Nagawa H, Muto T: High proliferative activity is
associated with dysplasia in ulcerative colitis. Dis
Colon Rectum 43(Suppl), S34-S39, 2000.
7. Kyo K, Parkes M, Takei Y, Nishimori H, Nagawa H,
Baba S, Muto T, Lathrop GM, Nakamura Y.
Association of ulcerative colitis with rare VNTR alleles of the human intestinal mucin gene, MUC3.
Human Molecular Genetics 8, 307-311, 1999.
8. Shinozaki M, Muto T, Suzuki K, Matsuda K,
Yokoyama T, Watanabe T, Masaki T, Sato H, Araki
S, Nagawa H. Chronic active disease reflects cancer
risk in ulcerative colitis. Jpn J Cancer Res 90, 10661070, 1999.
9. Fu CG, Tominaga O, Nagawa H, Nita ME, Masaki T,
Ishimaru G, Higuchi Y, Tsuruo T, Muto T. Role ofp53 and p21/WAF1 detection in patient selection for
preoperative radiotherapy in rectal cancer patients.
Dis Colon Rectum 41, 68-74, 1998.
10. Tominaga O, Nita ME, Nagawa H, Muto T. Screening
for APC mutation based on detection of truncated
APC proteins. Dig Dis Sci 43, 306-310, 1998.
11. Muto T, Nagawa H, Watanabe T, Masaki T, Sawada
T. Colorectal carcinogenesis. Dis Colon Rectum40(Suppl), S80-S85, 1997.
12. Tominaga O, Nita ME, Nagawa H, Fujii S, Tsuruo T,
Muto T. Expression of cell cycle regulators in humancolorectal cancer cell lines. Jpn J Cancer Res 88, 855860, 1997.

Chemotherapy
13. Nozawa H, Tsukui H, Nishida K, Yakumaru K,
Nagawa H, Sekikawa T. Dihydropyrimidine dehydrogenase expression in preoperative biopsy and surgically resected specimens of gastric carcinoma.
Cancer Chemother Pharmacol 49, 267-73, 2002.
14. Takenoue T, Nagawa H, Matsuda K, Fujii S, Nita ME,
Hatano K, Kitayama J, Tsuruo T, Muto T. Relation
between thymidylate synthase expression and survival in colon carcinoma, and determination of
appropriate application of 5-fluorouracil by immunohistochemical method. Annals of Surgical Oncology
7, 193-198, 2000.
15. Nita ME, Ono-Nita SK, Tsuno N, Tominaga O,
Takenoue T, Sunami E, Kitayama J, Nakamura Y,
Nagawa H. Bcl-XL antisense sensitizes human coloncancer cell line to 5-fluorouracil. Jpn J Cancer Res 91,
825-832, 2000.
16. Saito S, Tsuno N, Nagawa H, Sunami E, Zhengxi J,
Osada T, Kitayama J, Shibata Y, Tsuruo T, Muto T.
Expression of platelet-derived endothelial cell
growth factor correlates with good prognosis inpatients with colorectal carcinoma. Cancer 88, 42-49,
2000.

248

17. Seto Y, Nagawa H, Mori M, Tsuruo T, Muto T. Effectof 5-fluorouracil on gastrointestinal carcinogenesis
induced by N-methyl-N’-nitro-N-nitrosoguanidine inrats. Dig Dis Sci 44, 75-78, 1999.
18. Nita ME, Nagawa H, Tominaga O, Tsuno N, Fujii S,
Sasaki S, Fu CG, Takenoue T, Tsuruo T, Muto T. 5fluorouracil induces apoptosis in human colon cancer
cell lines with modulation of Bcl-2 family proteins. Br
J Cancer 78, 986-992, 1998.
19. Tsai WS, Nagawa H, Muto T. Differential effects ofpolyunsaturated fatty acids on chemosensitivity of
NIH3T3 cells and its transformants. Int J Cancer 70,
357-361, 1997.

Immunology
20. Osada T, Nagawa H, Takahashi T, Tsuno NH,
Kitayama J, Shibata Y. Dendritic cells cultured inanti-CD40 antibody-immobilized plates elicit a highly
efficient peptide-specific T-cell response. J
Immunother 25, 176-84, 2002.
21. Hasebe H, Sato K, Yanagie H, Takeda Y, Nonaka Y,
Takahashi TA, Eriguchi M, Nagawa H. Bcl-2, Bcl-XL
and c-FLIP (L) potentially regulate the susceptibilityof human peripheral blood monocyte-derived dendritic cells to cell death at different developmental
stages. Biomed Pharmacother 56, 144-51, 2002.
22. Osada T, Nagawa H, Kitayama J, Tsuno NH, Ishihara
S, Takamizawa M, Shibata Y. Peripheral Blood
Dendritic Cells, but Not Monocyte-Derived Dendeitic
Cells, Can Augment Human NK Cell Function.
Cellular Immunology 213, 14-23, 2001.
23. Nakayama H, Kitayama J, Muto T, Nagawa H.
Characterization of intracellular cytokine profile ofCD4(+) T cells in peripheral blood and tumor-draining lymph nodes of patients with gastrointestinal
cancer. Jpn J of Clin Oncology 30, 301-305, 2000.
24. Kitayama J, Hidemura A, Saito H, Nagawa H. Shearstress affects migration behaviour of polymorphonuclear cells arrested on endothelium. Cell Immunology
203, 39-46, 2000.
25. Kitayama J, Ikeda S, Kumagai K, Saito H, Nagawa H.
Alpha-6-beta-1 integrin (VLA-6) mediates leukocytes
tether and arrest on laminin under physiologicalshear flow. Cell Immunology 199, 97-103, 2000.
26. Ishihara S, Nieda M, Kitayama J, Osada T, Yabe T,
Kikuchi A, Koezuka Y, Porcelli SA, Tadokoro K,
Nagawa H, Juji T. Alpha-glycosylceramides enhance
the antitumor cytotoxicity of hepatic lymphocytes
obtained from cancer patients by activating CD3CD56+ NK cells in vitro. J Immunol 165, 1659-1664,
2000.
27. Ishihara S, Nieda M, Kitayama J, Osada T, Yabe T,
Ishikawa Y, Nagawa H, Muto T, Juji T. CD8+NKRP1A+ T cells preferentially accumulate in humanliver. Eur J Immunol 29, 2406-2413, 1999.
Metastasis
28. Nakayama H, Kitayama J, Nagawa H. Rat gastric adenocarcinoma cell line BV9 avidly adheres to lymphat-ic endothelium under lymphatic flow condition. J
Exp Clin Cancer Res 21, 289-94, 2002.
29. Yano H, Kitayama J, Hatano K, Tsuno N, Osada T,
Watanabe T, Tsuruo T, Muto T, Nagawa H.
Clustered cancer cells show a distinct adhesion
behavior from single cell form under physiologicalshear conditions. J Exp Clin Cancer Res 20, 407-12,
2001.
30. Sunami E, Tsuno N, Osada T, Saito S, Kitayama J,
Tomozawa S, Tsuruno T, Shibata Y, Muto T, Nagawa
H. MMP-1 is a prognostic marker for hematogenous
metastasis of colorectal cancer. Oncologist 5, 108114, 2000.
31. Kitayama J, Tsuno N, Sunami E, Osada T, Muto T,
Nagawa H. E-selectin can mediate the arrest type ofadhesion of colon cancer cells under physiologicalshear flow. Eur J Cancer 36, 121-127, 2000.
32. Tomozawa S, Nagawa H, Tsuno N, Hatano K, OsadaT, Kitayama J, Sunami E, Nita ME, Ishihara S, Yano
H, Tsuruo T, Shibata Y, Muto T. Inhibition of
haematogenous metastasis of colon cancer in miceby a selective COX-2 inhibitor, JTE-522. Br J Cancer
81, 1274-1279, 1999.
33. Kitayama J, Nagawa H, Tsuno N, Osada T, Hatano K,
Sunami E, Saito H, Muto T. Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow. Br J Cancer 80, 1927-1934, 1999.
34. Maeda M, Nagawa H, Maeda T, Koike H, Kasai H.
Alcohol consumption enhances liver metastasis incolorectal carcinoma patients. Cancer 83, 1483-1488,
1998.

Molecular biology
35. Sasaki S, Nakamura T, Arakawa H, Mori M,
Watanabe T, Nagawa H, Croce CM. Isolation andcharacterization of a novel gene, hRFI, preferentiallyexpressed in esophageal cancer. Oncogene, 21, 502430, 2002.
36. Uchida H, Shinoura N, Kitayama J, Watanabe T,
Nagawa H, Hamada H. Caspase-8 gene transduction
augments radiation-induced apoptosis in DLD-1
cells. Biochem Biophys Res Commun 292, 347-54,
2002.
37. Kazama S, Ajioka Y, Watanabe H, Watanabe T,
Nagawa H. Not infrequent K-ras mutations in
depressed-type early colorectal carcinomas larger
than 10 mm. Jpn J Cancer Res 93, 178-83, 2002.
38. Kato M, Yano K, Matsuo F, Saito H, Katagiri T,
Kurumizaka H, Yoshimoto M, Kasumi F, Akiyama F,
Sakamoto G, Nagawa H, Nakamura Y, Miki Y.
Identification of Rad51 alteration in patients withbilateral breast cancer. J Hum Genet 45, 133-137,
2000.
39. Umetani N, Sasaki S, Watanabe T, Ishigami H, Ueda
E, Nagawa H. Diagnostic primer sets for microsatellite instability optimized for a minimal amount ofdamaged DNA from colorectal tissue samples.
Annals Surg Oncol 7, 276-280, 2000.

40. Ishiguro T, Nagawa H, Naito M, Tsuruo T. Analysis
of novel metastasis-associated gene TI-227. Jpn J
Cancer Res 91, 390-394, 2000.

Stomach and esophagus
41. Ishiguro T, Ishiguro C, Ishiguro G, Nagawa H.
Midazolam sedation for upper gastrointestinalendoscopy: comparison between the states ofpatients in partial and complete amnesia.
Hepatogastroenterology 49, 438-40, 2002.
42. Nita ME, Nagawa H, Tominaga O, Tsuno N, Hatano
K, Kitayama J, Tsuruo T, Domene CE, Muto T. p21
Waf1/Cip1 expression is a prognostic marker in curatively resected esophageal squamous cell carcinoma,
but not p27Kip1, p53, or Rb. Annals Surg Oncol 6,
481-488, 1999.
43. Seto Y, Nagawa H, Muto Y, Kaizaki S, Kitayama J,
Muto T. Preliminary report on local resection withlymphadenectomy for early gastric cancer. Br J Surg86, 526-528, 1999.
44. Fujii S, Tominaga O, Nagawa H, Tsuno N, Nita ME,
Tsuruo T, Muto T. Quantative analysis of the cyclin
expression in human esophageal cancer cell lines. J
Exp Clin Cancer Res 17, 491-496, 1998.
45. Seto Y, Nagawa H, Muto T. Results of extended
lymph node dissection for gastric cancer cases with
N2 lymph node metastasis. Int Surg 82, 257-261,
1997.
46. Nagawa H, Seto Y, Kobori O, Muto T. An experienceof treatment for patients with thoracic esophageal
cancer invading adjacent organs. Jpn J Clin Oncol 27,
248-250, 1997.
47. Nagawa H, Seto Y, Muto T. Recent advances in gastric cancer. Digestion 58(Suppl 1), 62-64, 1997.
48. Nagawa H, Seto Y, Nakatsuka T, Kaizaki S, Muto T.
Microvascular anastomosis for additional blood flowin reconstruction after intrathoracic esophageal carcinoma surgery. Am J Surg 173, 131-133, 1997.
49. Seto Y, Nagawa H, Muto T. Prognostic significance of
non-gastric malignancy after treatment of early gastric cancer. Br J Surg 84, 418-421, 1997.
50. Seto Y, Nagawa H, Muto T. Impact of lymph nodemetastasis on survival in early gastric cancer. World J
Surg 21, 186-190, 1997.

249

Department of Dermatology
Outline and Research Objectives
Department of Dermatology has been chaired by Kunihiko Tamaki M.D.Ph.D. since
1994. The Department of Dermatology celebrated its 100th anniversary in 1990. Originally it
was founded as the Department of Dermatology and Urology, which also encompassed
venereology. In 1946 the Department of Dermatology was separated from that of Urology.
Department of Dermatology had its branch department in Branch Hospital for about 50
years until these two departments joined last year. A professor, two associate professors,four lecturers and nine associates take part in in-patient and out-patient cares as well as
research and teaching activities. We usually have around 10 residents and 8 students of doctoral PhD. course. Thirty doctors who basically belong to our department are currently out
in affiliated hospitals mainly engaged in clinical works there. Additionally there are four
staff members abroad in the US and involved in advanced research activities in cell biology
and molecular biology as postdoctoral fellow.
We have specialized out-patient clinic in which some of doctors who are in affiliated hospitals also participate and each specialized service reflects its own research field in a diseaseoriented manner.
Of course these specialized groups performing their clinical and reseach activities are notexclusive, and there are increasing communications in our department as well as with otherdepartments. Specialized out-patient clinic include the following; atopic dermatitis, psoriasis, collagen diseases including systemic sclerosis, SLE and dermatomyositis, skin surgery
and laser surgery including malignant melanoma, squamous cell carcinoma and basal cell
carcinoma, and infection especially fungal infection. These clinical groups are divided into
three main research groups;
Immunology and allergology group, 2) collagen disease group and 3) skin surgery group.
Immunology and allergology group engaged in atopic dermatitis and psoriasis clinic andfocuses on Langerhans cell and keratinocyte biology research including cytokine andchemokine. Collagen group engaged in collagen disease clinic and focuses mechanisms TGFβ and collagen. Skin surgery group engaged in skin surgery and laser surgery clinic andfocuses of tumor growth, metastasis, fibrosis and dermatoscopic clinical study. Researchgroups are maintained by associate professor or lecturer. These senior investigators have ten
to fifteen year experience as dermatologist and more that seven year experience of researchin Japan as well as in U.S.A. They have one to three associates and students of Ph.D. course
to extend their research. Professors participate and understand the research activities in thisdepartment through conferences which are usually held once to twice a month by eachresearch group.

Faculties and Students
Professor and Chairman Kunihiko Tamaki M.D. Ph.D.(1994-)
Associate Professors Kanako Kikuchi M.D. Ph.D.
Akihiko Asahina M.D. Ph.D.
LecturerMayumi Komine M.D. Ph.D.
Hironobu Ihn M.D. Ph.D.
Hidehisa Saeki M.D. Ph.D.
Takahiro Watanabe M.D. Ph.D.
Associate .................................9
Graduate student ....................8
Secretary .................................3

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Past Research and Major Accomplishments
1) Immunology and allergology group:
We established a method to purify
murineLangerhans cells(LC), which comprise from
one to three percentage of epidermal cells, over 95%
purity in each experiment and conducted a series ofexperiments. We found that murine LC produced IL12 which is a key cytokine for Th1 induction and that
IL-12 production was inhibited by GM-CSF andenhanced by TGF-b1. Furthermore we found prionrelated protein was expressed in LC as well as ker-atinocytes. Prion-related protein is maintained on LC
after culture suggesting its participation of LC in
peripheral inoculation of prion disease. With regards
to atopic dermatitis (AD) we found that lesional skinof NC/Nga mice, which exhibit AD like skin lesion,shows enhanced expression of Th2 chemokine
TARC/CCL17 and MDC/ CCL22 and their receptor
CCR4. We extended this to human AD and other skindiseases such as bullous pemphigoid, an autoimmune
blistering disease and mycosis fungoides, cutaneous T
cell lymphoma, all exhibit hypereosinophilia and highserum IgE and found that TARC, MDC and CCR4 are
involved in these diseases.
2) Collagen disease group:
TGF-β has been implicated in the pathogenesis offibrosis. In collaboration with skin surgery group we
showed upregulated expression of TGF-β receptors inlesional skin of fibrosis such as systemic sclerosis andlocalized scleroderma and that upregulated expressionof TGF-β receptors is implicated in fibrosis. Fibroblast
proliferation is also important in fibrosis as well as
wound healing. We demonstrated that fibroblast proliferation is mediated via extracellular signal related
kinase (ERK)-dependent pathway. We also studied theexpression of tissue inhibitor of metalloproteinases(TIMPs) and showed that TIMP2 was upregulated byIL-4 via p-38 mitogen-activated protein kinasedependent pathway. With regards to clinical research
we investigated the prevalence and clinical significance of various autoantibodies in collagen diseases.
We also studied the levels of various cytokines andadhesion molecules and their significance.
3) Skin surgery group:
We investigated progressive and metastatic factors
in malignant melanoma and other skin tumors. We
found dysregulated expression of TGF-β and its receptor in basal cell carcinoma and also found that patternof basal cell keratin 14 expression is a possible marker
for tumor progression in Bowen’s disease. We also
reported TIMP-1 and TIMP-2 differently regulate thegrowth of human melanoma cell lines. With regards
to clinical research we established criteria for the diagnosis of pigmented plantar nevi which is useful to differentiate pigmented nevi from early acral lentiginous
melanoma. We also proposed criteria to differentiate
Hutchingson’s sign seen in malignant melanoma fromsubungual nevus.

Current Research1) Immunology and allergology group:
Using the TGF-β primed LC we are trying to
induce Th1 instead of Th2. We succeeded in inducing

Th1 in vitro and trying to induce Th1 in vivo. We continue to characterize murine LC and found LC express
Toll-like receptor (TLR)-2 3 4 and 9. We are trying to
induce Th1 using these receptors. From the results ofmouse and human study we are trying to establish
K14-TARC transgenic mice to further characterize thesignificance of TARC expression in the epidermis.
With regards to clinical research we are analyzing
gene polymorphism of AD and proriasis such as
Eotaxin, TARC, IL-13 and IL-12. We are also investigating the CTACK/CCL27 expression of AD and psoriasis. We are analyzing the human peripheral blood
dendritic cells (DC) for the expression of cutaneous
lymphocyte associated antigen (CLA), fucosyltransferase VII, CCR4 and CCR10, and their function.
2) Collagen disease group:
We are studying the interaction of transcription
factors Sp 1, Smad 3 and p300/CBP and the significance of these transcriptional factors in TGF-β
induced collagen gene upregulation. PKC is importantin collagen accumulation, thus we are studying theregulation of collagen deposition by PKC especially
PKC a and PKCd The regulation of TGF-β receptors by
various cytokines such as EGF and TNF-α are now
being studied. We found overexpression of aVb5 andVb3 integrin on fibroblasts from fibrotic tissue. The
function of this is under investigation using stabletransfectants of integrins. We also are studying theregulation of tenasin gene expression by IL-13, PDGF
and TGF-β.
3) Skin surgery group:
We are now trying to establish the significance ofsentinel lymph mode biopsy in the clinic and trying
to find the metastatic factors in malignant melanoma.
We are analyzing chemokine and chemokine receptor
expression of primary and metastatic melanoma. We
also are studying the effect of narrow band UVB on
human melanocytes in order to understand theenhanced pigmentation seen in patients receiving narrow band UVB therapy.

Future Prospects
Immunology and allergology group: We will continue the murine LC study to further clarify the characteristics of LC and their participation in skin diseases. We will also study the possibility to use LC fortherapy as well as DC from human peripheral blood.
We will try to find novel gene products using purified
LC and analyze their function. We will establish othertransgenic mice such as K-14- CTACK to further analyze the participation of chemokine in skin diseases.
With regards to clinical research we will further
examine other cytokine and chemokine in skin dis-251eases such as AD and psoriasis and try to use theirantagonist for therapy.
Collagen disease group: To further analyze themolecular mechanisms of TGF-β induced collagengene expression, the cross talk of PI3 kinase andSmad pathway will be determined. Significance ofintegrin expression in fibrosis will be determined.
The mechanisms of EGF and FK506 on the expressionof collagen gene expression will be studied in conjunction with the therapeutic approach.
Skin surgery group: DC therapy for malignant
tumors using DC from peripheral blood and skin resident LC will be investigated. We will also analyze
chemokine / chemokine receptor expression in
growth and metastasis of skin tumors.

Research Grants from
1. The Ministry of Education, Science and Culture(A,2002-2005)“Study on the dendritic cells and chemokine in thepathogenesis of skin diseases”
2. The Health Science Research Grants from the
Ministry of Health, Welface and Labor (2002-)“Study to identify organ specific molecules in thepathogenesis of skin diseases”
3. The Health Science Research Grants from the
Minictry of Health, Welface and Labor (2001-2002)“Basic Research for Atopic Dermatitis using Dendritic
cells as a tool”
4. The Ministry of Education, Science and Culture (B.
1157063 1999-2000)“The study of skin specific T cells in the pathogenesis of skin diseases”
5. The Ministry of Education, Scince and culture(B,11470179,1999-2001)“The study to establish Langerhans cell cell line andits use for treatment”

Select Publications
1. Kakinuma T, Wakugawa M, Nakamura K, Hino H,
Matsushima K, Tamaki K. High level of TARC (thymus and activation-regulated chemokine/CCL17) inblister fluid and sera of patients with bullous pemphigoid. Br J Dermatol, in press.
2. Sugaya M, Nakamura K, Watanabe T, Asahina A,
Yasaka N, Koyama Y, et al: Expression of cellularprion-related protein by murine Langerhans cells andkeratinocytes. Journal of Dermatology Sci. 28:126134,2002
3. Hattori N, Komine M, Yano S, Kaneko T, Hanakawa
Y, Hashimoto K, Tamaki K.: Interferon-g, a strong
suppressor of cell proliferation, induces upregulationof karatin K6, one of the inflammatory- and proliferation-associated keratins. J Invest Dermatol 119:403-10, 2002.
4. Kakinuma T, Nakamura K, Wakugawa M, Mitsui H,
Tada Y, Saeki H, Torii H, Komine M, Asahina A,

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Tamaki K. Serum macrophage-derived chemokine(MDC) levels are closely related with the diseaseactivity of atopic dermatitis. Clin Exp Immunol, 127:
270-3, 2002.
5. Ihn H, Yamane K, Asano Y, Kubo M, Tamaki K. IL-4
upregulates the tissue inhibitor of metalloproteinase2 in dermal fibroblasts via the p38 mitogen-activatedprotein kinase-dependent pathway. J Immunol 168:
1895-902, 2002.
6. Tamaki K, Nakamura K: The role of lymphocyte inhealthy and eczematous skin. Curr Opinion Allergy
Clin. Immunol 1:455-60,2001
7. Kubo M, Ihn H, Yamane K, Asano Y, Jinnin M,
Tamaki K: Differential expression of transforming
growth factor-beta receptors in squamous cell carcinoma. Br J Dermatol. 145: 840-2, 2001
8. Kubo M, Ihn H, Kuwana M, Yamane K, Yazawa N,
Tamaki K: Prevalence in myositis of antibodies recognizing anti-U3 RNA probably in a novel complex
with 22/25 kD protein and not fibrillarin. Clin Exp
Immunol. 126: 339-44, 2001
9. Yazawa N, Ihn H, Yamane K, Kubo M, Fujimoto M,
Kikuchi K, Soma Y, Tamaki K: Elevated circulating
soluble CD30 levels in patients withpolymyositis/dermatomyositis. Br J Dermatol. 145:
676-8, 2001
10. Hoashi T. Kadono T. Kikuchi K. Etoh T. Tamaki K:
Differential growth regulation in human melanoma
cell lines by TIMP-1 and TIMP-2. Biochem Biophys
Res Commun. 288: 371-9, 2001
11. Komine M. Okinaga M. Takeda F. Nashiro K.
Kikuchi K. Murakami T. Soma Y. Tamaki K: Patternsof basal cell keratin 14 expression in Bowen’s disease: a possible marker for tumour progression. Br J
Dermatol. 145: 223-8, 2001
12. Wakugawa M. Nakamura K. Kakinuma T. Onai N.
Matsushima K. Tamaki K: CC chemokine receptor 4
expression on peripheral blood CD4+ T cells reflects
disease activity of atopic dermatitis. J Invest
Dermatol. 117: 188-96, 2001
13. Tamaki K, Sugaya M, Tada Y, Uasaka N, Uehira M,
Nishimoto H, Nakamura K: Epidermal and dermal
gamma-delta T cells. Chem Immunol 79:43-51,2001
14. Asano Y. Ihn H. Yamane K. Yazawa N. Kubo M.
Fujimoto M. Tamaki K: Clinical significance of surfactant protein D as a serum marker for evaluating
pulmonary fibrosis in patients with systemic sclerosis. Arthritis Rheum. 44: 1363-9, 2001
15. Asahina A. Tada Y. Nakamura K. Tamaki K:
Griseofulvin has a potential to modulate the expression of cell adhesion molecules on leukocytes andvascular endothelial cells. Int Immunopharmacol. 1:
75-83, 2001
16. Kubo M. Ihn H. Yamane K. Tamaki K: Up-regulated
expression of transforming growth factor beta receptors in dermal fibroblasts in skin sections frompatients with localized scleroderma. Arthritis
Rheum. 44: 731-4, 2001
17. Tada Y. Asahina A. Nakamura K. Miyazono K.
Tomura M. Fujiwara H. Tamaki K: Transforming

growth factor-beta up-regulates CD40-engaged IL-12
production of mouse Langerhans cells. Eur J
Immunol. 31: 294-300, 2001
18. Kakinuma T. Nakamura K. Wakugawa M. Mitsui H.
Tada Y. Saeki H. Torii H. Asahina A. Onai N.
Matsushima K. Tamaki K: Thymus and activationregulated chemokine in atopic dermatitis: Serum thymus and activation-regulated chemokine level isclosely related with disease activity. J Allergy Clin
Immunol. 107: 535-41, 2001
19. Yazawa N. Ihn H. Yamane K. Etoh T. Tamaki K: The
successful treatment of prurigo pigmentosa withmacrolide antibiotics. Dermatology. 202: 67-9, 2001
20. Ihn H. Yamane K. Kubo M. Tamaki K: Blockade ofendogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased
expression of transforming growth factor beta receptors. Arthritis Rheum. 44: 474-80, 2001
21. Kawabata Y. Ohara K. Hino H. Tamaki K: Two kindsof Hutchinson’s sign, benign and malignant. J Am
Acad Dermatol. 44: 305-7, 2001
22. Wakugawa M. Hayashi K. Nakamura K. Tamaki K:
Evaluation of mite allergen-induced Th1 and Th2
cytokine secretion of peripheral blood mononuclear
cells from atopic dermatitis patients: association
between IL-13 and mite-specific IgE levels. J
Dermatol Sci. 25: 116-26, 2001
23. Asahina A. Tada Y. Nakamura K. Tamaki K:
Colchicine and griseofulvin inhibit VCAM-1 expression on human vascular endothelial cells - evidence
for the association of VCAM-1 expression withmicrotubules. J Dermatol Sci. 25: 1-9, 2001
24. Watanabe T. Nakamura K. Wakugawa M. Kato A.
Nagai Y. Shioda T. Iwamoto A. Tamaki K:
Antibodies to molluscum contagiosum virus in thegeneral population and susceptible patients. Arch
Dermatol. 136: 1518-22, 2000
25. Ihn H. Tamaki K: Increased phosphorylation of transcription factor Sp1 in scleroderma fibroblasts: association with increased expression of the type I collagen gene. Arthritis Rheum. 43: 2240-7, 2000
26. Ihn H. Tamaki K: Oncostatin M stimulates thegrowth of dermal fibroblasts via a mitogen-activatedprotein kinase-dependent pathway. J Immunol. 165:
2149-55, 2000
27. Wakugawa M. Nakamura K. Hino H. Toyama K.
Hattori N. Okochi H. Yamada H. Hirai K. Tamaki K.
Furue M: Elevated levels of eotaxin and interleukin-5
in blister fluid of bullous pemphigoid: correlation
with tissue eosinophilia. Br J Dermatol. 143: 112-6,
2000
28. Nakamura K. Imakado S. Takizawa M. Adachi M.
Sugaya M. Wakugawa M. Asahina A. Tamaki K:
Exacerbation of pustulosis palmaris et plantaris after
topical application of metals accompanied by elevated levels of leukotriene B4 in pustules. J Am Acad
Dermatol. 42: 1021-5, 2000

29. Ihn H. Tamaki K: Competition analysis of the humanalpha2(I) collagen promoter using synthetic oligonucleotides. J Invest Dermatol. 114: 1011-6, 2000
30. Tada Y. Asahina A. Nakamura K. Tomura M.
Fujiwara H. Tamaki K: Granulocyte/macrophagecolony-stimulating factor inhibits IL-12 production ofmouse Langerhans cells. J Immunol. 164: 5113-9,
2000
31. Ihn H. Sato S. Fujimoto M. Igarashi A. Yazawa N.
Kubo M. Kikuchi K. Takehara K. Tamaki K:
Characterization of autoantibodies to endothelial
cells in systemic sclerosis (SSc): association with pulmonary fibrosis. Clin Exp Immunol. 119: 203-9, 2000
32. Yazawa N. Kikuchi K. Ihn H. Fujimoto M. Kubo M.
Tamaki T. Tamaki K: Serum levels of tissue inhibitorof metalloproteinases 2 in patients with systemicsclerosis. J Am Acad Dermatol. 42: 70-5, 2000
33. Yamane K. Ihn H. Kubo M. Yazawa N. Kikuchi K.
Soma Y. Tamaki K: Increased serum levels of solublevascular cell adhesion molecule 1 and E-selectin inpatients with localized scleroderma. J Am Acad
Dermatol. 42: 64-9, 2000
34. Salgado CG, Nakamura K, Sugaya, M, Tada Y,
Asahina A, Fukada, S, Koyama Y, Irie S, Tamaki K.
Differential effects of cytokines and immunosuppressive drugs on CD40, B7-1, and B7-2 expression on
purified epidermal Langerhans cells. J Invest
Dermatol 113: 1021-7, 1999.
35. Kanda N, Tamaki K. Ganglioside GD1b suppresses
immunoglobulin production by human peripheral
blood mononuclear cells. Exp Hematol 27: 1487-93,
1999.
36. Sugaya M, Nakamura K, Tamaki K. Interleukins 18
and 12 synergistically upregulate interferon-g production by murine dendritic epidermal T cells. J
Invest Dermatol 113: 350-4, 1999.
37. Salgado CG, Nakamura K, Sugaya M, Tada Y,
Asahina A, Koyama Y, Irie S, Tamaki K. Functional
CD40 ligand is expressed on epidermal Langerhans
cells. J Leukocyte Biol 66: 281-5, 1999.
38. Kubo M, Ihn H, Sato S, Kikuchi K, Tamaki K.
Prevalence and antigen specificity of anti-histone
antibodies in patients with polymyositis/dermatomyositis. J Invest Dermatol 112: 711-5, 1999.
39. Watanabe T, Tsuchida T, Kanda N, Mori K, Hayashi
Y, Tamaki K. Anti-a-fodrin antibodies in Sjogren syndrome and lupus erythematosus. Arch Dermatol 135:
535-9, 1999.
40. Kanda N, Tamaki K. Estrogen enhances
immunoglobulin production by human PBMCs. J
Allergy Clin Immunol 103: 282-8, 1999.
41. Kanda N, Tsuchida T, Tamak K. Estrogen enhancement of anti-double-stranded DNA antibody andimmunoglobulin G production in peripheral bloodmononuclear cells from patients with systemic lupus
erythematosus. Arthritis Rheum 42: 328-37, 1999.
42. Kubo M, Kikuchi K, Nashiro K, Kakinuma T, Hayashi
N, Nanko H, Tamaki K. Expression of fibrogenic
cytokines in desmoplastic malignant melanoma. Br J
Dermatol 139: 192-7, 1998.

253

43. Kanda N, Tamak K. Ganglioside CQ1b enhances Ig
production by human PBMCs. J Allergy Clin
Immunol 102: 813-20, 1998.
44. Kubo M, Kikuchi K, Fujimoto M, Tamaki K. Serum
concentration of carboxyterminal propeptide of type1 procollagen and tissue inhibitor of metaloproteinase 1 in patients with dermatomyositis. Arch
Dermatol Res 290: 253-7, 1998.
45. Kawabata Y, Tamaki K. Distinctive dermatoscopic
features of acral lentiginous melanoma in situ fromplantar melanocytic nevi and their histopathologic
correlation. J Cutan Med Surg 2: 199-204, 1998.
46. Kikuchi K, Kubo M, Kadono T, Yazawa N, Ihn H,
Tamaki K. Serum concentrations of vascularendothelial growth factor in various collagen diseases. Br J Dermatol 139: 1049-51, 1998.
47. Watanabe T, Tsuchida T, Ito Y, Kanda N, Ueda Y,
Tamaki K. Annular erythema associated with lupus
erythematosus / Sjogren’s syndrome. J Am Acad
Dermatol 36: 214-8, 1997.
48. Kanda N, Tsuchida T, Tamaki K. Testosterone suppresses anti-DNA antibody production in peripheralmononuclear cells from patients with systemic lupus
erythematosus. Arthritis Rheum 40: 1703-11, 1997.
49. Kikuchi K, Kadono T, Furue M, Tamaki K. Tissue
inhibitor of metalloproteinase-1 (TIMP-1) may be an
autocrine growth factor in scleroderma fibroblasts. J
Invest Dermatol 108: 281-4, 1997.
50. Furue M, Kato M, Nakamura K, Nashiro K, Kikuchi
K, Okochi H, Miyazono K Tamaki K. Dysregulated
expression of transforming growth factor β and its
type I and II receptors in basal cell carcinoma. Int J
Cancer 71: 505-9, 1997.

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Department of Plastic andReconstructive Surgery
Outline and Research Objectives
The Department of Plastic and Reconstructive Surgery was established in 1960 as thefirst independent clinical department in Japan. Clinical activities were initially focused oncongenital anomalies and skin surgery. In the 1970’s, however, surgical techniques such as
microsurgery, craniofacial surgery, tissue expansion, etc. were developed, and our activities
were significantly expanded so that could lead the world in the field of the free tissue transfers, head and neck cancer reconstruction, hand surgery, craniomaxillofacial surgery, etc.
Recently, cosmetic surgery and aesthetic dermatology were also added to our clinical field,
and now we have the greatest number of patients for cosmetic purposes among all universities in Japan. Current research objectives are tissue and cell engineering from somatic stem
cells, hair regeneration, anti-aging effects of hormones on skin, embryonic development ofcongenital anomaly, and application of retinoids to skin and keloids.

Faculties and Students:
Professor and Chair Kiyonori Harii, M.D. (1989-)
Associate Professors Hirotaka Asato, M.D. (1998-)
Lecturer
Kotaro Yoshimura, M.D. (1998-)
Associates ...............................4
Postdoctral Fellows.................5
Graduate Students ..................4
Secretaries ...............................2

Past Research and Major Accomplishments
Professor Harii has developed a number of surgical
techniques in reconstructive microsurgery such asmuscle transplantation for facial reanimation in facialparalyzed patients, and microsurgical reconstructionof head and neck cancer patients. These activities
were published in various international medical journals and textbooks. He accepted a number of trainees
from countries all over the world, who studied andmastered microsurgery in our laboratory.

Current Research
We have several research projects, both basic andclinical. In basic research, molecular and cellularapproaches to reveal the mechanism of congenital
anomalies, such as cleft lips and palates, ear deformities, and craniofacial deformities, are ongoing. We are
seeking genes which can cause those anomalies. In
addition, influences of hormones, especially estrogen,on skin aging are being investigated. Genes, which
can be upregulated or downregulated by estrogen indermal fibroblasts, are being investigated by microarray technique. We are trying to determine the mechanism by which estrogen affects the chronologicalaging of skin. The third one is on hair regeneration.
We harvest and culture dermal papilla cells from hairfollicles, which can transform epidermal stem cells
into hair follicles. We have tried to determine criticalfactors released by dermal papilla cells in order toapply to a practical treatment of alopecia. The last one
is mesenchymal stem cells extraction from lipoaspirates. We are trying to transform the stem cells into
adipocytes, chondrocytes, osteoblasts, dermal fibroblasts, and others for clinical use. The optimal protocols to culture and transform the stem cells have been
investigated.
Clinically, we have attempted to establish a classification of pigmented skin lesions. Also, the mechanism of hyperpigmentation and rational therapies are
currently being established. Clinical effects of achemopreventional therapy for keloids using retinoids
are now under estimation.

Future Prospects
Our research projects will be more focused on tissue and cell engineering using somatic (mesenchymal)
stem cells in the future. Cosmetic augmentation ofsoft tissue such as breasts, cheek, and eyelids may beclinically available using adipose cells or tissues produced by mesenchymal stem cells extracted fromlipoasipates. The stem cells could be applied to therapies of a wide variety of diseases such as hepatic dysfunction, arterial sclerosis, joint cartilage problems,
myocardial infarction, leukemia, etc.

255

Research Grants
1) Kotaro Yoshimura, Grants-in aid for scientific research(B) 2002-2003, Molecular biological research on
MMPs and TIMPs expression of human keloids.
2) Hirotaka Asato, Grants-in aid for scientific research (B)2002-2003, Study on a specific skeletogenic potentialof the cranial neural crest cells.
3) Kiyonori Harii, Grants-in aid for scientific research (A),
2000-2001, Evaluation of rejection at the transplantation of cultured cell and induction of local torelance
without systemic immunosuppuression.
4) Kotaro Yoshimura, Grants-in aid for scientific research(B), 2000-2001, Molecular biological research on
actions of retinoids on wound healing and pigmentation in skin.
5) Shinichi Wakita, Grants-in aid for scientific research(B), 1999-2000, Mesenchymal stem cells; actions inwound healing and application to tissue engineering.

Select Publications
1. Takushima A, Asato H, Harii K, Masashi S.
Simultaneous harvest of intercostal nerves and elevation of rectus abdominis musculocutaneous flap for
facial nerve cable grafting. Plast Reconstr Surg 110,541-544, 2002.
2. Yoshimura K, Asato H, Jejurikar SS, Cederna PS,
Urbanchek MG, Kuzon WM Jr. The effect of two
episodes of denervation and reinnervation on skeletal muscle contractile function. Plast Reconstr Surg
109, 212-219, 2002.
3. Takushima A, Harii K, Asato H, Yamada A.
Neurovascular free-muscle transfer to treat facial
paralysis associated with hemifacial microsomia.
Plast Reconstr Surg 109, 1219-1927, 2002.
4. Kimata Y, Uchiyama K, Sakuraba M, Ebihara S,
Hayashi R, Haneda T, Onitsuka T, Asakage T,
Nakatsuka T, Harii K. Velopharyngeal function after
microsurgical reconstruction of lateral and superior
oropharyngeal defects. Laryngoscope 112, 10371042, 2000.
5. Harii K., Asato H.: Facial reanimation. The
Unfavorable Result in Plastic Surgery, 3rd Ed. (ed. by
Goldwyn, R.M., Cohen, M.N.), Lippincott, Williams
and Wilkins, Philadelphia, 2001
6. Kitano Y, Yoshimura K, Uchida G, Sato K, Harii K.
Pretreatment with topical all-trans-retinoic acid isbeneficial for wound healing in genetically diabetic
mice. Arch Dermatol Res 293, 515-521, 2001.
7. Ichioka S, Nakatsuka T, Ohura N, Sato Y, Harii K.
Clinical use of amrinone (a selective phosphodiesterase III inhibitor) in reconstructive surgery. Plast
Reconstr Surg 108, 1931-1937, 2001.
8. Nagase T, Nakamura S, Harii K, Osumi N. Ectopically
localized HNK-1 epitope perturbs migration of the
midbrain neural crest cells in Pax6 mutant rat. Dev
Growth Differ 43, 683-692, 2001.
9. Takushima A, Harii K, Asato H, Nakatsuka T, Kimata
Y. Mandibular reconstruction using microvascular

256

free flaps: a statistical analysis of 178 cases. Plast
Reconstr Surg 108, 1555-1563, 2001.
10. Yoshimura K, Tsukamoto K, Okazaki M, Virador
VM, Lei TC, Suzuki Y, Uchida G, Kitano Y, Harii K.
Effects of all-trans retinoic acid on melanogenesis inpigmented skin equivalents and monolayer culture ofmelanocytes. J Dermatol Sci 27, S68-75, 2001.
11. Nakagawa M, Miyagoe-Suzuki Y, Ikezoe K, Miyata Y,
Nonaka I, Harii K, Takeda S. Schwann cell myelination occurred without basal lamina formation inlaminin alpha2 chain-null mutant (dy3K/dy3K) mice.
Glia 35, 101-110, 2001.
12. Yoshimura K, Harii K, Masuda Y, Takahashi M,
Aoyama T, Iga T. Usefulness of a narrow-bandreflectance spectrophotometer in evaluating effects
of depigmenting treatment. Aesthetic Plast Surg 25,
129-133, 2001.
13. Nagase T, Shimoda Y, Sanai Y, Nakamura S, Harii K,
Osumi N.: Differential expression of two glucuronyltransferases synthesizing HNK-1 carbohydrate epitope in the sublineages of the rat myogenic progenitors. Mech Dev 98, 145-149, 2000,.
14. Kimata Y, Uchiyama K, Ebihara S, Saikawa M,
Hayashi R, Haneda T, Ohyma W, Kishimoto S, Asai
M, Nakatsuka T, Harii K.: Postoperative complications and functional results after total glossectomy
with microvascular reconstruction. Plast Reconstr
Surg 106, 1028-1035, 2000.
15. Kimata Y, Uchiyama K, Ebihara S, Sakuraba M, Iida
H, Nakatsuka T, Harii K. Anterolateral thigh flap
donor-site complications and morbidity. Plast
Reconstr Surg 106, 584-589, 2000.
16. Ichioka S, Nakatsuka T, Ohura N, Sato Y, Harii K.:
Topical application of amrinone (a selective phosphodiesterase III inhibitor) for relief of vasospasm. J SurgRes 93, 149-155, 2000.
17. Gonda K, Nakaoka T, Yoshimura K, OtawaraHamamoto Y, Harrii K. Heterotopic ossification ofdegenerating rat skeletal muscle induced by adenovirus-mediated transfer of bone morphogenetic protein-2 gene. J Bone Miner Res 15, 1056-1065, 2000.
18. Yoshimura K, Harii K, Aoyama T, Iga T. Experience
with a strong bleaching treatment for skin hyperpigmentation in Orientals. Plast Reconstr Surg 105,
1097-1108, 2000.
19. Yoshimura K, Ouchi K, Wakita S, Uda K, Harii K.
Surgical correction of cryptotia with superiorly based
superficial mastoid fascia and skin paddle. Plast
Reconstr Surg 105, 836-841, 2000.
20. Kimata Y, Uchiyama K, Ebihara S, Kishimoto S, Asai
M, Saikawa M, Ohyama W, Haneda T, Hayashi R,
Onitsuka T, Nakatsuka T, Harii K. Comparison of
innervated and noninnervated free flaps in oral
reconstruction. Plast Reconstr Surg104, 1307-1313,
1999.
21. Shimoda Y, Tajima Y, Nagase T, Harii K, Osumi N,
Sanai Y. Cloning and expression of a novel galactoside beta1, 3-glucuronyltransferase involved in thebiosynthesis of HNK-1 epitope. J Biol Chem 274,
17115-17122, 1999.

22. Kimata Y, Uchiyama K, Sekido M, Sakuraba M, Iida
H, Nakatsuka T, Harii K. Anterolateral thigh flap for
abdominal wall reconstruction. Plast Reconstr Surg
103, 1191-1197, 1999.
23. Nakatsuka T, Harii K, Takushima A, Yoshimura K,
Ichioka S, Sugasawa M, Ichimura K, Seto Y, Nagawa
H. Prefabricated free jejunal transfer: a new reconstructive technique for high pharyngeal defects. Plast
Reconstr Surg103, 458-64, 1999.
24. Harii K. Asato H. Nakatsuka T. Ebihara S.
Reconstructive plastic surgery in cancer treatment:
surgery for quality of life. Jap Soc Clin Oncol 4, 193201, 1999.
25. Yoshimura K, Harii K. A regenerative change during
muscle adaptation to denervation in rats. J Surg Res
81, 139-146, 1999.
26. Gonda K, Okamoto H, Takuwa N, Yatomi Y, Okazaki
H, Sakurai T, Kimura S, Sillard R, Harii K, Takuwa Y.
The novel sphingosine 1-phosphate receptor AGR16
is coupled via pertussis toxin-sensitive and -insensitive G-proteins to multiple signalling pathways.
Biochem J 337, 67-75, 1999.
27. Harii,K. : Free groin flap reconstruction of severeburn neck constructure. Grabb’s encyclopedia offlaps second edition (eds. Strauch,B. et al.) vol.1,
pp.478-480, Lippincott-Raven, Philadelphia, 1998.
28. Harii,K. Asato,H. : Microneurovascular free gracilis
muscle transfer for facial reanimation. Grabb’s encyclopedia of flaps second edition (eds. Strauch,B. etal.) vol.1, pp.521-524, Lippincott-Raven, Philadelphia,
1998.
29. Harii,K. : Microvascular free transfer of the groin skinflap. Grabb’s encyclopedia of flaps second edition(eds. Strauch,B. et al.) vol.II, pp.1110-1111,
Lippincott-Raven, Philadelphia, 1998.
30. Harii,K. : Microvascular free transfer of a groin skinflap. Grabb’s encyclopedia of flaps second edition(eds. Strauch,B. et al.) vol.III, pp.1328-1330,
Lippincott-Raven, Philadelphia, 1998.
31. Hirabayashi S, Sugawara Y, Sakurai A, Harii K, Park
S. Frontoorbital advancement by gradual distraction.
Technical note. J Neurosurg 89, 1058-61, 1998.
32. Kimata Y, Uchiyama K, Ebihara S, Nakatsuka T, Harii
K. Anatomic variations and technical problems of theanterolateral thigh flap: a report of 74 cases. Plast
Reconstr Surg 102, 1517-1523, 1998.
33. Yoshimura K, Harii K, Asato H, Ueda K, Yamada A.
Immunohistochemical analysis of clinically transplanted muscles. J Surg Res 79, 31-38, 1998.
34. Harii K, Asato H, Yoshimura K, Sugawara Y,
Nakatsuka T, Ueda K. One-stage transfer of the latissimus dorsi muscle for reanimation of a paralyzed
face: a new alternative. Plast Reconstr Surg 102, 941951, 1998.
35. Takushima A, Kitano Y, Harii K. Osteogenic potentialof cultured periosteal cells in a distracted bone gap in
rabbits. J Surg Res 78, 68-77, 1998.
36. Yoshimura K, Kuzon WM, Harii K. Myosin heavy
chain expression in skeletal muscle autografts underneural or aneural conditions. J Surg Res 75, 135-147,
1998.
37. Ueda K, Harii K, Asato H, Yamada A. Neurovascular
free muscle transfer combined with cross-face nerve
grafting for the treatment of facial paralysis in children. Plast Reconstr Surg 101, 1765-1773, 1998.
38. Ichioka S, Nakatsuka T, Sato Y, Shibata M, Kamiya
A, Harii K. Amrinone, a selective phosphodiesterase
III inhibitor, improves microcirculation and flap survival: a comparative study with prostaglandin E1. J
Surg Res 75, 42-48, 1998.
39. Kitano Y, Kurihara H, Kurihara Y, Maemura K, Ryo Y,
Yazaki Y, Harii K. Gene expression of bone matrix
proteins and endothelin receptors in endothelin-1deficient mice revealed by in situ hybridization. J
Bone Miner Res 13, 237-244, 1998.
40. Nakaoka T, Gonda K, Ogita T, Otawara-Hamamoto
Y, Okabe F, Kira Y, Harii K, Miyazono K, Takuwa Y,
Fujita T. Inhibition of rat vascular smooth muscle
proliferation in vitro and in vivo by bone morphogenetic protein-2. J Clin Invest 100, 2824-2832, 1998.
41. Ichioka S, Shibata M, Kosaki K, Sato Y, Harii K,
Kamiya A. Effects of shear stress on wound-healing
angiogenesis in the rabbit ear chamber. J Surg Res
72, 29-35, 1997.
42. Ueda K, Harii K, Yamada A. Free vascularized double
muscle transplantation for the treatment of facial
paralysis. Plast Reconstr Surg 95, 1288-1296, 1995.
43. Yamada A, Harii K, Ueda K, Asato H, Tanaka H.
Versatility of a cross-leg free rectus abdominis flap
for leg reconstruction under difficult and unfavorable
conditions. Plast Reconstr Surg 95, 1253-1257, 1995.
44. Kimata Y, Uetake M, Tsukada S, Harii K. Follow-up
study of patients treated for ingrown nails with thenail matrix phenolization method. Plast Reconstr
Surg 95, 719-724, 1995.
45. Ueda K, Harii K, Yamada A. Electromyographic studyof functional recovery of free vascularized muscles
grafted to the face. Plast Reconstr Surg 95, 296-304,
1995.
46. Kawashima T, Yamada A, Ueda K, Asato H, Harii K.
Tissue expansion in facial reconstruction. Plast
Reconstr Surg 94, 944-950, 1994.
47. Ueda K, Harii K, Yamada A. Free neurovascular muscle transplantation for the treatment of facial paralysis using the hypoglossal nerve as a recipient motor
source. Plast Reconstr Surg 94, 808-817, 1994.
48. Komuro Y, Takato T, Harii K, Yonehara Y. The histologic analysis of distraction osteogenesis of themandible in rabbits. Plast Reconstr Surg 94, 152-159,
1994.
49. Ueda K, Harii K, Yamada A. Long-term follow-up of
nerve conduction velocity in cross-face nerve grafting
for the treatment of facial paralysis. Plast Reconstr
Surg 93, 1146-1149, 1994.
50. Nakatsuka T, Harii K, Yamada A, Asato H, Ebihara S.
Versatility of a free inferior rectus abdominis flap forhead and neck reconstruction: analysis of 200 cases.
Plast Reconstr Surg 93, 762-769, 1994.

257

Department of Oral andMaxillofacial Surgery
Outline and Research Objectives
Department of Oral and Maxillofacial Surgery, commenced by Dr. Hisashi Ishihara in
1900, is one of the oldest departments in Graduate School of Medicine, University of Tokyo.
Professor Takato is the 7th professor in our department. The department has been the centerof the clinical and basic research in oral and maxillofacial region in Japan. Congenital anomalies, jaw deformities, benign and malignant oral tumors, facial bone fractures, temporomandibular joint diseases, and dental treatment in systemic diseases are mainly treated andresearched in our department. Multidisciplinary treatment teamed by plastic surgeons, oral
surgeons, orthodontists, prothodontists, etc. is characteristic and has performed excellent
results in clinical works. In research fields, we have mainly performed the experimental
studies on the regenerative capacity of tissues, especially bone, periosteum, cartilage, perichondrium, vessels, nerve, skin, etc. At present, we are focusing on tissue engineering inresearch works especially in bone, cartilage, vessels. Professor Takato has established
Division of Tissue Engineering in Tokyo University Hospital and our department has two
endowment departments: Department of Cartilage and Bone Regeneration (Menicon
Co.,Ltd.) and Department of Clinical Vascular Regeneration (Daiichi Pharmaceutical Co.,
Ltd.) in Tissue Engineering Division. These departments have 1 associate professor, 1staff,
and 4 graduate students in each. These staff are focusing on translational research works inmaxillofacial regions.

Research Objectives
1) Multidisciplinary treatment of facial deformities in patients with cleft lip and palate orother congenital maxillofacial anomalies
2) Multidisciplinary treatment of dentomaxillofacial deformities, fractures and temporomandibular diseases3) Multidisciplinary treatment of malignant tumors in head and neck region4) Reconstruction using bone and cartilage grafts in maxillofacial region5) Clinical and research works on distraction osteogenesis in maxillofacial region6) Basic research of bone metabolism7) Basic research on osteogenic capacity of periosteum8) Basic research on capacity of perichondrial regeneration
9) Basic research on growth plate
10) Tissue engineering on bone, cartilage, and vessels, etc

Faculties and Students
Professor and Chair

Tsuyoshi Takato, M.D., PhD.
(since 1996)
Associate Professor Takafumi Susami, D.D.S., PhD.
Lecturer
Yoshiyuki Mori, D.D.S., PhD.
Tomoaki Eguchi, M.D., PhD.
Tetsuya Yoda, D.D.S., PhD.
Hisako Hikiji, D.D.S., PhD.
Associate ...............................10
Clinical Stuff............................7
Resident ..................................9
Graduate student ..................12
Research student.....................1

258

Secretary .................................2

Past Research and Major Accomplishments
1. Clinical research:
1) Multidisciplinary treatment of facial deformities
in patients with cleft lip and palate or other congenital maxillofacial anomalies
2) Multidisciplinary treatment of dentomaxillofacial
deformities, fractures and temporomandibulardiseases
3) Multidisciplinary treatment of malignant tumors
in head and neck region4) Facial bone lengthening by distraction osteogenesis5) Correction of facial deformity in cleft lip andpalate patients
6) Speech problems in cleft lip and palate patients
7) Facial growth in craniofacial anomalies
8) Evaluation of the treatment outcomes in patientswith cleft lip and/or palate
9) Combined surgical-chemical-radiological treatment
for malignant tumors
10) Development of dental implant
11) Surgical-orthodontic treatment of dentofacial
deformities
12) Effects of arthrocentesis or therapeutic exercisesfor temporomandibular disorders
13) Effects of masticatory force on facial form
14) Non-surgical treatment system for facial bone fractures
2. Basic and experimental research:
1) Osteogenic capacity of periosteum2) Capacity of perichondrial regeneration
3) Osteogenic capacity of growth plate4) Development of various types of new skin flaps
5) Metabolism of poly ADP-ribose in DNA repair andcell differentiation
6) Gene analysis of congenital anomalies of oral andmaxillofacial region7) Effect of free radicals on bone metabolism
8) Intracellular calcium handling on osteoblasts9) Differentiation mechanism of osteoblasts in termsof cell cycle molecule10) Functional analysis on domains of P130Cas in actincytoskeleton organization, cell migration, and
Src transformation
11) Osteochondrogenic differentiation of bone marrow derived mesenchymal stem cells by spheroid
culture12) Cloning of the 5’Upstream Region of the Rat p16
Gene and Its Role in Silencing
13) Studies on relationship between dystrophin associated protein and advanced heart failure14) Mandibular lengthening by floating bone method
15) Periodontal tissue regeneration on dental implants16) Characterization of skin derived multipotent stem
cells, especially differentiation mechanism into
neuronal cell17) Bone and cartilage repair in dentomaxillofacial
region using tissue engineering technique259

Current ResearchMultidisciplinary treatment
Transplantation (carterige,bone,etc)

Oral surgeon

Distraction osteogenesis

Plastic surgeon

Dental Implant

Orthodontists

Orthognathic Surgery
Orthodontic treatment

Prothodontist

Cancer treatment

Translational Research
Tissue Engineering
Division of Tissue Engineering
Bone and Cartilage Regenerative Medicine (Takeda Chemical Industories, Ltd.)
Cartilage and Bone Regeneration (Menicon Co.,Ltd.)

School of Enginnering
Scaffold

Clinical Vascular Regeneration (Daiichi Pharmaceutical Co., Ltd.)Drug delivery system

Hematopoietic Regeneration(Kirin Brewery Company, Limited)

School of medicine
Clinical Renal Regeneration(Mochida Pharmaceutical Co.,Ltd.)

Corneal Tissue Regeneration(HOYA Healthcare Corporation)

Internal Medicine
Vascular Surgery
Orthopedic Surgery
Gene Therapy
Drug delivery system
etc.

International Medical Center Research InstituteNational Cancer Center(Gene therapy, Stem Cell)

Kitazato Medical School (Stem Cell)
National Institute of Advanced Industrial Science and Technology
KOKEN Co.,Ltd260

Future Prospects
Our department has been the center of the treatment and research in dentomaxillofacial diseases forthe last century in Japan. For decade years, we established the system of the multidisciplinary treatment
for diseases in dentaomaxillofacial region. We are
now in the next step to develop the new treatment
for deficiency of dentomaxillofacial region using tissue-engineering technique. For this purpose, Professor
Takato established the Division of Tissue Engineeringin Tokyo University Hospital in 2001. We have been
researching the development of the materials, tissues
and organs which are constructed with the tissueengineering technique. Three-dimensional construction of cartilage and bone with neovascularization is
our most important theme to investigate. These
regenerated tissues would repair the deficiency of thedentomaxillofacial region without the harvest of grafted materials from the donor sites. To achieve thistranslational research, we are cooperating with several
companies and Ministries.

Research Grants
The Ministry of Edition, Science, Culture and Technology
Research Grant B2 (1995-1996)
Research Grant B1 (1997-1998)
Research Grant B2 (1997-1998)
Research Grant B2 (1999−2001)
Grant for development of advanced medicine (2002-2004)

Select Publications
1. Harii K., Ebihara S., Ono I., Saito H., Terui S., andTakato T.: Pharyngoesophageal reconstruction usinga fabricated forearm free flap. Annals of Plastic
Surgery, 85: 463-474, 1985
2. Takato T., Ono I., Ebihara S., and Saeki T.: Repair of
stenosed tracheostoma. Journal of Oto-RhinoLaryngology & its Related Specialties, 47: 299-302,
1985
3. Takato T., Ono I., Ebihara S., and Matsumoto T.:
Reconstruction of the oral commissure. Oral Surgery,
Oral Medicine, Oral Pathology, 62: 132-134, 1986
4. Takato T., Harii K., Nakatsuka T., Ueda K., andOhtake T.: Vascularized periosteal graft : An experimental study using two different forms of tibial
periosteum in rabbits. Plastic and Reconstructive
Surgery, 78: 489-497, 1986
5. Takato T., Harii K., Ebihara S., Ono I., Yoshizumi T.,
and Nakatsuka T.: Oral and pharyngeal reconstruction using the free forearm flap. Archives of
Otolaryngology, 113: 873-879, 1987
6. Takato T., Harii K., and Nakatsuka T.: The development of bone after perichondrial grafting : An experimental study using ear and rib perichondrium in rab-

bits. British Journal of Plastic Surgery, 40: 636-641,
1987
7. Takato T., Harii K., and Nakatsuka T.: The sequential evaluation of bone scintigraphy : an analysis ofrevascularised bone grafts. British Journal of Plastic
Surgery, 41: 262-269, 1988
8. Takato T., Harii K., and Nakatsuka T.: Osteogenic
capacity of vascularized periosteum : experimental
study using rib periosteum in rabbits. British Journalof Plastic Surgery, 41: 528-532, 1988
9. Takato T., Harii K., Nakatsuka T., and Ohtake T.:
Experimental study of vascularized bone :Quantitative analysis of bone scintigraphy and histology. Journal of Reconstructive Microsurgery, 4:391-397, 1988
10. Takato T., Ohsone H., and Tsukakoshi H.:
Treatment of severe microstomia by swallowing
caustic soda. Oral surgery, Oral medicine, Oralpathology, 67: 20-24, 1989
11. Takato T., Kamei M., Kato K., and Kitano I.: Cleft
palate in the Beckwith-Wiedemann syndrome.
Annals of Plastic Surgery, 22: 347-349, 1989
12. Takato T., Itoh M., Yokota M., Kyoku I., Kitano M.,
Misuhara T., and Sakamoto K.: Delayed thoracic closure after cardiac surgery in infants. British Journalof Plastic Surgery, 44: 106-108, 1991
13. Takato T., Zuker R.M., and Turley C.B.:
Prefabrication of skin flaps using vein graft : anexperimental study in rabbits. British Journal of
Plastic Surgery, 44: 593-598, 1991
14. Takato T., Nakai H., Yonehara Y., Takeda H., Susam
P., Kitano Y., and Kato K.: Binder’s syndrome :Peculiarities in Japanese patients. Annals of Plastic
Surgery, 27: 371-381, 1991
15. Takato T., Zuker R.M., and Turley C.B: Viability andversatility of arterialized venous perfusion flaps andprefabricated flaps : an experimental study in rabbits. Journal of Reconstructive Microsurgery, 8: 111119, 1992
16. Takato T., Komuro Y., Yonehara Y., and Zuker R.M.:
Viability and versatility of arterialized venous perfusion flaps and prefabricated flaps : an experimental
study in rabbits. British Journal of Plastic Surgery,48: 111-119, 1993
17. Takato T., Komuro Y., Yonehara Y., and Zuker R.M.:
Prefabricated venous flaps : an experimental study in
rabbits. British Journal of Plastic Surgery, 46: 122126, 1993
18. Takato T., Harii K., Komuro Y., and Yonehara Y.:
Experimental study on growth of epiphysial plate :free graft in rabbits. British Journal of Plastic Surgery,46: 416-420, 1993
19. Komuro Y., Takato T., Yamada A., and Yonehara Y.:
Experimental study of prefabricated flaps using vein
grafts. Journal of Reconstructive Microsurgery, 9:373-380, 1993
20. Takato T., Harii K., Komuro Y., Yonehara Y., andSusami T.: Mandibular lengthening by gradual distraction : analysis using accurate skull replicas.
British Journal of Plastic Surgery, 46: 686-693, 1993

261

21. Komuro Y., Takato T., Harii K., and Yonehara Y.:
The histological analysis of distraction osteogenesisof mandible in rabbits. Plastic and Reconstructive
Surgery, 94: 152-159, 1994
22. Takato T., Harii K., Yonehara Y., Komuro Y., Susami
T., and Uoshima K.: Correction of the cleft nasal
deformity with an L-shaped iliac bone graft. Annalsof Plastic Surgery, 33: 486-493, 1994
23. Komori Y., Takato T., and Akagawa T.: Use of alaser-hardened three dimensional replica for simulated surgery. Journal of Oral and Maxillofacial Surgery,52: 516-521, 1994
24. Takato T., Yonehara Y., and Susami T.: Early correction of the nose in unilateral cleft lip patients using
an open method : A 10-year review. Journal of Oraland Maxillofacial Surgery, 53: 28-33, 1995
25. Takato T., Yonehara Y., and Susami T.: Columella
lengthening using a cartilage graft in the bilateralcleft lip-associated nose : Choice of cartilage according to age. Journal of Oral and Maxillofacial Surgery,53: 149-157, 1995
26. Takato T., Yonehara Y., Mori Y., Sakamoto Y., andSusami T.: Use of Cantilever Iliac Bone Grafts for
Reconstruction of Cleft Lip-Associated Nasal
Deformities. Journal of Oral and Maxillofacial
Surgery, 53: 757-762, 1995
27. Komori T., Takato T., and Yokoyama K.: Integrationof dental models in a three-dimensional replica.
Journal of Oral and Maxillofacial Surgery, 53: 621624, 1995
28. Komori T., Matsumoto K., Yokoyama K., and Takato
T.: A Morphological Study of Bone Cuts with
Aluminium Oxide Particles. Japanese Journal of Oral
Diagnosis/ oral Medicine. 8: 208-212, 1995
29. Takato T., Yonehara Y., Susami T., and Uoshima K.:
Modification of the Abbe Flap for Reconstruction fo
the Vermilion Tubercle and Cupid’s Bow in Cleft Lip
Patients. Journal of Oral and Maxillofacial Surgery,
54: 256-261, 1996
30. Komori T., Yokoyama K., Takato T., and Matsumoto
K.: Clinical application of the erbium:YAG laser forapicoectomy. Journal of Endodontics, 23:748-750，
1997
31. Nozaki T., Masutani M., Sugimura T., Takato T., andWakabayashi K.: Abrogation of G1 arrest after DNA
damages is associated with constitutive expressionof Mdm2, Cdk4, and Irf1 mRNAs in the BALB/c 3T3
A31 Variant 1-1 Clone. Biochemical & BiophysicalResearch Communications, 233: 1997
32. Hikiji H., Wee Soo Shin, Oida S., Takato T, Koizumi
T, and Toyooka T: Direct action of nitric oxide on
osteoblastic differentiation. FEBS Letters, 410:238242, 1997
33. Yonehara Y., Takato T., Harii K., Hirabayashi S.,
Susami T., Komori T., Matsumoto S., Hikiji H., andNakatsuka T.: Secondary lengthening of the reconstructed mandible using a gradual distraction technique-two case reports. British Journal of Plastic
Surgery, 51: 356-358, 1998

262

34. Nakatsuka T., Harii K., Yamada A., Yonehara Y.,
Takato T., Kawahara N., Sakaki T., Yamasoba T.,
Nibu K., and Ebihara S.: Immediate Free Flap
Reconstruction for Head and Neck Pediatric
Malignancies. Annals of Plastic Surgery, 40(6): 594599, 1998
35. Sakata Y., Tokunaga K., Yonehara Y., Bannai M.,
Tsuchiya N., Susami T., and Takato T.: Significant
association of HLA-B and HLA-DRB1 alleles withcleft lip with or without cleft palate. Tissue
Antigens, 53: 147-152, 1999
36. Takushima A., Susami T., Nakatsuka T., Harii K.,
and Takato T.: Multi-Bracket Appliance inManagement of Mandibular Reconstr uction with
Vascularized Bone Graft. Japanese Journal of ClinicalOncology, 29: 119-126, 1999
37. Yonehara Y., Takato T., Matsumoto S., Nakatsuka
T.: Distraction of scarred soft tissue before secondarybone grafting. International Journal of Oral
Maxillofacial Surgery, 28: 347-348, 1999
38. Yonehara Y., Nakatsuka T., Ichioka I., Takato T.,
Matsumoto S., and Yamada A.: Intramuscular haemangioma of the anterior chest wall. British Journalof Plastic Surgery, 53: 257-259，2000
39. Yonehara Y., Takato T., Matsumoto S., Mori Y.,
Nakatsuka T., and Hikiji H.: Correction of cleft lip
nasal deformity in Orientals with a cantilevered iliacbone graft. Scandinavian Journal of Plastic andReconstructive Surgery and Hand Surgery, 34: 137143，2000
40. Yonehara Y., Takato T., Susami T., and Mori Y.:
Correction of Micrognathia Attributable to Ankylosisof the Temporomandibular Joint Using a GradualDistraction Technique: Case Report. Journal of Oraland Maxillofacial Surgery, 58:1415-1418，2000
41. Chikazu D., Shindo M., Iwasaka T., Katagiri M.,
Manabe N., Takato T., Nakamura K., and Kawaguchi
H.: A Novel Synthetic Triazolotriazepine Derivative
JTT-606 Inhibits Bone Resorption by DownRegulation of Action and Production of Bone
Resorptive Factors. Journal of Bone Miner Research,
15(4):674-682，2000
42. Hikiji H., Shin WS, Koizumi T., Takato T., Susami T.,
Koizumi Y., Okai-Matsuo Y., and Toyooka T.:
Peroxynitrite production by TNF-alpha and IL-1beta:
implication for suppression of osteoblastic differentiation. American Journal of Physiology Endocrinology & Metabolism, 278: E1031-1037，
2000
43. Hikiji H., Takato T., Matsumoto S., and Mori Y.:
Experimental Study of Reconstruction of the
Temporomandibular Joint Using a Bone Transport
Technique. Journal of Oral and Maxillofacial Surgery,
58: 1270-1276，2000
44. Chikazu D., Hakeda Y., Nemoto K., Itabashi A.,
Takato T., Kumegawa M., Nakamura K., andKawaguchi H.: Fibroblast growth factor-2 directly
stimulates mature osteoclasts activity through autophosphorylation of FGF receptor 1. Journal of
Biological Chemistry2000, 275: 31444-31450，2000

45. Katagiri M., Hakeda Y., Chikazu D., Ogasawara T.,
Takato T., Kumegawa M., Nakamura K., andKawaguchi H. :Mechanism of Stimulation of
Osteoclastic Bone Resorption through Gas6／Tyro3,
a Receptor Tyrosine Kinase Signaling in Mouse
Osteoclasts. Journal of Biological Chemistry2001,
276(10):b7376-7382, 2001
46. Eguchi T., Asato H., Takushima A., Takato T., andHarii K. : Surgical repair for congenital macrostomia:
A vermilion square flap method. Annals of Plastic
Surgery 47:629-635, 2001
47. Chikazu D., Katagiri M., Ogasawara T., Ogata N.,
Shimoaka T., Takato T., Nakamura K., andKawaguchi H.: Regulation of osteoclast differentiation by fibroblast growth factor 2: Stimulation ofreceptor activator of nuclear factorκB ligand/osteoclast differentiation factor expression in osteoblasts
and inhibition of macrophage colony-stimulating factor function in osteoclast precursors. Journal of Bone& Mineral Research, 16(11): 2074-2081, 2001
48. Sakai N., Tokunaga K., Yamazaki Y., Shida H., Sakata
Y., Susami T., Takato T. and Uchinuma E. : Sequence
analysis of fibroblast growth factor receptor 2
FGFR2) in Japanese patients with craniosynostosis.
Journal of Craniofacial Surgery, 12: 580-585, 2001
49. Nozaki T., Fujihara H., Kamada N., Ueda O., TakatoT., Nakagama H., Sugimura T., M.J.A., Suzuki H.,
and Masutani M. ：Hyperploidy of embryonic
fibroblasts derived from Parp-1 knockout mouse.
Proceeding of the Japan Academy, 77B(6) : 121124,2001
50. Jinhong Huang, Hamasaki H., Nakamoto T., Honda
H., Hirai H., Saito M., Takato T., Sakai R. :Differential regulation of cell migration, actin stressfiber organization and cell transformation by functional domains of Cas Journal of Biological Chemistry277(30): 27265-27272, 2002

263

Department ofOrthopaedic Surgery
Outline and Research Objectives
Our department was established in 1906 as the first department of orthopaedic surgery
in Japan. Since then our efforts have been dedicated to responding to the needs of patientsfor orthopaedic care and to related research. We have pioneered handicapped children’scare, developed new and innovative surgical techniques, and invented arthroscopy which is
now used worldwide.
Our department seeks to elucidate the molecular and genetic backgrounds of bone andcartilage disorders including osteoporosis, osteoarthritis, and joint destruction in rheumatoid arthritis. To achieve this, we utilize the newest methodologies, and with the knowledge gained, we are working to develop groundbreaking treatments for these conditions,such as bone and cartilage regeneration. At the same time we are attempting to establish a
non-invasive analyzing system to evaluate the mechanical property of the skeletal system
and a computer-guided operating system to put to use our findings of the last half decade.

Faculty and Students
Professor and Chair

Kozo Nakamura, M.D., Ph.D.
(1998-)
Associate Professor Hiromi Oda, M.D., Ph.D.
Yoshio Takatori, M.D., Ph.D.
Lecturer
Isao Ohnishi, M.D., Ph.D.
Atsushi Seichi, M.D., Ph.D.
Takahiro Goto, M.D., Ph.D.
Hiroshi Kawaguchi, M.D., Ph.D.
Hiroshi Okazaki, M.D., Ph.D.
Associate ...............................12
Postdoctoral Fellow ................1
Graduate student ..................25
Secretary .................................3

Past Research and Major Accomplishments
1. Regulation of anabolic and catabolic bonemetabolism by fibroblast growth factor-2 (FGF-2)
We have had achieved notable advances in laboratory and clinical research on cytokines / growth factors in bone. Perhaps our most important contribution has been in defining the actions of FGF-2 onbone. We have reported the anabolic action of FGF-2
on bone formation using several physiological andpathological animal models of both rodents and primates. Our efforts in this area have led to studies ofclinical application of FGF-2 to fracture healing andosteoporosis. The involvement of FGF-2 on bone
resorption has also been investigated and this may
possibly be involved in the joint destruction byrheumatoid arthritis.

264

2. Molecular mechanism of age-related bone loss
(A novel aging suppressor gene: klotho)
Reverse genetic analysis revealed that mice deficient in the klotho gene exhibited bone loss with low
turnover which is characteristic of human osteoporosis with aging. Using a forward genetic approach, we
found that two polymorphisms at the human klotho
locus are correlated with bone density in postmenopausal women, especially in their older years
and independent of race, suggesting that the klotho
gene may be involved in bone loss with aging.
3. Involvement of insulin signaling in bone anabolic action
Through clinical studies we found that the severityof ossification of the posterior longitudinal ligamentof the spine (OPLL) is associated with insulin secretory response due to impairment of the response toinsulin in its target tissues. The importance of insulin
signaling in the anabolic bone metabolism was confirmed by reverse genetic approach on knock-out miceof the insulin receptor substrates IRS-1 and IRS-2,
which are essential intracellular signaling molecules of
insulin. It was shown that IRS-1 maintains boneturnover while IRS-2 is needed to maintain the predominance of bone formation over bone resorption;
the integration of these two signalings causes a potent
bone anabolic action by insulin.
4. Molecular mechanism of osteoclast differentiation in rheumatoid arthritis (RA)Recent studies have revealed that a TNF-α superfamily cytokine, receptor activator of nuclear factor-kB
ligand (RANKL) plays a pivotal role in osteoclast differentiation and activation. We found that RANKL ishighly expressed in synovial fibroblasts obtained
from RA patient synovial tissues, and critically implicated in the bone and joint destruction of RA.
5. Gene transfer to osteoclasts and gene therapy
We recently established a gene transduction system into mature osteoclasts using adenovirus vectors,
and successfully regulated osteoclast function byintroducing several genes that modulate the function
and survival. Protooncogene product c-Src is a nonreceptor type tyrosine kinase which is indispensablefor osteoclast activation. The kinase activity of c-Src isregulated by another cytoplasmic tyrosine kinase Csk(C-terminal Src kinase). Introduction of csk gene into
osteoclasts by the adenovirus vector completely disrupted the cytoskeletal organization of the cells, andstrongly suppressed their bone-resorbing activity.
Using the adenovirus vector-mediated gene transduction system, we also found that the Ras-ERK pathway
is critical for the survival of osteoclasts.
6. Gene therapy of arthritic joint destruction
using adenovirus vectors
Adenovirus vectors are effective not only in vitro
but also in vivo gene delivery into osteoclasts. Local
injection of Csk adenovirus reduced IL-1-inducedbone destruction in calvarial bone. When injected into
arthritic joints, adenovirus vectors efficiently transduce synovial fibroblasts as well as osteoclasts. Csk
adenovirus inhibited proliferation of synovial fibroblasts and their proinflammatory cytokine production
in vitro, and intraarticular injection of the virus significantly ameliorated joint destruction in adjuvant
arthritis rats. These results demonstrate that the adenovirus vector system is a good therapeutic approachto arthritic bone destruction.
We also found that adenovirus vector-mediatedcsk gene transduction suppressed the tumor metastasis and constitutively active MEK1 gene recovered theparaplegia after spinal cord injury.
7. Regulation of bone homeostasis by RANKL and
IFNs (interferons)
Investigation of the regulation of osteoclastogenesis by the immune system showed the critical involvement of IFNs in bone metabolism. Mice deficient in
IFNGR1 (IFN-γ receptor) exhibited more severe bonedamage accompanied by enhanced osteoclastogenesis
when stimulated with lipopolysaccharide (LPS).
Activated T cells strongly inhibited osteoclastogenesis
via IFN-γ, and IFN-γ interfered with RANKL signaling
by inhibiting expression of TRAF6 (TNF receptor
associated factor 6). Thus, IFN-γ protects against T
cell-mediated inflammatory bone loss. In contrast,
mice deficient in IFNAR1 (IFN-α receptor, one of IFNα/β receptor components) spontaneously develop

marked osteopenia accompanied by enhanced osteoclastogenesis. RANKL induces IFN-β gene in osteoclast precursor cells and IFN-β inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for
osteoclastogenesis. Thus, IFN-β acts as a negative
feedback regulator of RANKL-induced osteoclastogenesis in physiological bone remodeling. Thus, IFN-γ
and IFN-β, both of which play pivotal roles in the
immune system, also function in the negative regulation of RANKL signaling via distinct mechanisms.

Current Research
1. Reverse and forward genetic approach to thepathophysiology of osteoarthritis
Osteoarthritis, a major skeletal disorder, is considered a collective result of heterogeneous etiopathologic factors affecting cartilage. We actually identified
two novel genes associated with chondrocyte differentiation and degradation: cystacin10 and cgk2. To
further determine the molecular background of thedisorder, we created an osteoarthritis model in miceby cutting ligaments in and around the knee joint.
Several knock-out or transgenic mice were subjected
to an operation to learn the involvement of themanipulated gene in the disorder. In addition, as aforward genetic approach, we are in the middle of the
genome-wide association study on the human knee
and hip osteoarthritis.
2. Gemone-wide association study of OPLL
Based on a reverse genetic study, we have foundthat nucleotide pyrophosphate (Npps) gene is related
to the incidence and progression of OPLL. Since OPLL
is a polygenic disease, we are conducting a genomewide association study of the condition in whichmore than 100,000 single nucleotide polymorphisms(SNPs) will be evaluated for their association with susceptibility to and severity of OPLL. DNA samples are
now being collected in a national project headed by
the presenter.
3. Molecular mechanism of age-related bone loss
(PPAR-γ)Considering that osteoblasts and adipocytes shareorigins in bone marrow mesenchymal cells, and thathuman aging is associated with a reciprocal increasein adipocytes and a decrease in osteoblasts in bonemarrow, PPAR-γ may be clinically involved in thepathophysiology of bone loss with aging as a suppressor of osteoblastogenesis. To identify the role ofendogenous PPAR-γ in vivo, we examined the bone of
PPAR-γ hetero knock-out mice, and found that bonemass in these mice increases with stimulation of265osteoblastogenesis from bone marrow progenitors
without affecting mature osteoblasts or osteoclast-lineage cells. The forward genetic approach beginningwith the screening of polymorphisms of the human
PPAR-γ gene is now underway.
4. Cloning master gene(s) of osteoclast differentiation
In an attempt to identify gene(s) that regulate
osteoclast differentiation, we are utilizing a molecularindexing technique, and have found several genesthat regulate osteoclast-specific promoter activity. We
are currently working on the function of the genes inosteoclasts.
5. Treating arthritic bone destruction by targeting
RANKL/RANK pathways
As mentioned above, RANKL/RANK pathways are
critically involved in pathological bone resorption,and therefore can be a good therapeutic target. The
effect of osteoprotegerin (OPG), a natural inhibitor of
RANKL, on pathological bone resorption is currently
being examined. In a preliminary study, local injection of recombinant human OPG into arthritic joints
effectively ameliorated the bone destruction in adjuvant arthritis rats.
We are also trying to establish a technology of
RANKL vaccination therapy, in which modified
RANKL is utilized to induce anti-RANKL self-antibody, which has neutralizing activity against self
RANKL, and therefore has a therapeutic effect onbone destruction.
6. Molecular mechanism of osteoclast apoptosis
Osteoclasts are terminally differentiated non-proliferating cells with a very short life span. We are now
trying to identify molecule(s) that induce osteoclast
apoptosis, and have found that a pro-apoptotic Bcl-2
family member Bim plays an essential role. In ourstudies on the role of small GTP-binding proteins on
osteoclast survival, Rac1 transduction was found to
prolong the survival.
7. Gene therapy of arthritic bone resorption
We recently found that adenovirus vectors carrying dominant negative Ras gene (AxRasDN) strongly
suppressed the proliferation and proinflammatory
cytokine production of synovial fibroblasts. We are
currently investigating the effect of AxRas DN on
arthritic bone destruction, and in a preliminary study,
found that this virus could significantly suppress joint
destruction in adjuvant arthritis rats.
8. Evaluation of mechanical properties of skeletal
system
A system of analyzing mechanical properties of a266

skeletal system has been required to clinically evaluate the efficacy of osteoporosis treatment and to
decide on a method or term of fracture treatment. We
are developing a non-invasive analyzing system invivo using CT based finite element analyses which
can make it possible to predict fracture load and location, which is based on the maximum principal stressfailure theory.
9. Investigation of adult neural progenitors as a
new therapeutic tool for damaged spinal cord
Seeking a therapeutic tool useful in the treatmentof the damaged spinal cord, we have investigatedadult endogenous neural progenitors, including stem
cells. Their widespread occurrence and proliferationin response to injury have been demonstrated. One of
their regulatory mechanisms in vivo, Notch signaling,is suggested from their molecular property. Thus,
genetic manipulations of endogenous progenitors insitu may enable the recruitment of their latent regenerative potential. Further advances of such strategies
may make possible significant structural repair of thedamaged spinal cord.
10. Development of a joint prosthesis with lessloosening
We are developing a new type of hip joint prosthesis whose surface is covered with a synthetic material,methacryloyloxyethyl phoshorylcholine (MPC),
resembling the human membrane phospholipid. We
have confirmed that the prosthesis successfully
decreases the friction index up to 1/5 of the conventional one. Due to the similarity of the material to living membrane, this may possibly elicit a less rejective
response causing loosening. This prosthesis will
improve the outcome of joint replacement surgery
and lead to a new era in osteoarthritis treatment.
11. Navigation robot for minimally invasive surgery
Image-guided surgery is gradually spreading withthe advancement of pre-surgical simulation using Xray CT or MR images to achieve minimally invasive
and safer surgical procedures. In cervical bone fixation
surgery, highly accurate positioning accuracy isrequired during drilling to avoid injuring the spinal
cord and major blood vessels. However, when using
an image-guided navigation system, we encounter difficulties in obtaining accurate “registration” between
the navigation results and a device such as a needle,
screw or drill; these difficulties arise mainly either
from a surgeon’s tremor or complicated spatial orientation relations. To overcome these problems, wehave developed the first prototype of a simple robot
having two degrees-of-freedom (2-DOF), which controls the orientation of a device. The characteristics of

the robot, low DOF, restricted range of movement,
and light weight, make it possible to use it in a clinicalsetting.

Future Prospects
1. Bone and cartilage regeneration
We plan to introduce a new type of bone and cartilage regeneration based not only on tissue engineering, but also on molecular and genetic biology.
Endochondral bone development is characterized by aprocess in which a cartilage mold is replaced by bone.
During this process, cartilage induces bone in theadjacent tissue. We have found that a subgroup of cartilage containing hypertrophic chondrocytes plays anessential role in this induction. In addition, thesechondrocytes induce vascular invasion. Based onthese two findings, we came up with a new strategy
to regenerate bone, which is a relatively well vascularized organ. Instead of separately regenerating boneand vasculature and subsequently combining andtransplanting them to create viable bone tissue, wehave proposed to graft hypertrophic chondrocytes tohave them induce both bone and vasculature simultaneously. To realize this unique strategy, we are trying
to improve methods to derive chondrocytes from various stem cells, differentiate them further into hypertrophic chondrocytes, and combine them with appropriate scaffolds to create new osteogenic-angiogenic
biomaterial.

2. Control of pathological bone destruction
In the future, we will be able to establish novel
treatments for pathological bone destruction, and theRANKL/RANK pathway can be a good therapeutic target. RANKL vaccination technology is a promisingpreventive therapy. By identifying the genes and signal transduction pathways that regulate osteoclast differentiation, activation, and survival, we will be able
to regulate bone resorption much more precisely andmeticulously. Adenovirus vector-mediated gene transduction will be a good means of gene therapy targeting osteoclasts by modulating intracellular signals.
3. Surgical navigation system with intuitive threedimensional display and navigation robot
We are developing a new surgical navigation system which superimposes the real, intuitive threedimensional (3-D) image of the patient’s internal
structure on the patient’s body, and helps surgeons toperform surgery. The system consists of a personal
computer, a lens array, a supporting stage, a liquid
crystal display and a half-silvered mirror. The 3-D
images are generated by real-time computer-generated
integral photography, and superimposed on thepatient’s body via a half-silvered mirror, as if they
were seen through the body. Because of the simplicity
and the intuitiveness of the navigation image, thissystem will become applicable for clinical use in thenear future in combination with the navigation robot
system described above.

Research Grants (Figure 1)

267

Select Publications (50)
1. Nakamura K, Kurokawa T, Aoyama I, Hanada K,
Tamura M, Kawaguchi H: Stimulation of bone formation by intraosseous application of basic fibroblast
growth factor in ovariectomized rats. Int Orthop 22:
49-54, 1998
2. Tanaka S, Takahashi T, Takayanagi H, Miyazaki T,
Oda H, Nakamura K, Hirai H, Kurokawa T:
Modulation of osteoclast function by adenovirus vector-induced epidermal growth factor receptor. J Bone
Miner Res 13: 1714-1720, 1998
3. Nakamura K, Matsushita T, Mamada K, Okazaki H,
Ou W, Okuma Y, Kurokawa T: Changes of callus
diameter during axial loading and after fixator
removal in leg lengthening. Arch Orthop Trauma
Surg 117: 464-467, 1998
4. Kato T, Kawaguchi H, Hanada K, Aoyama I, Hiyama
Y, Kuzutani T, Tamura M, Kurokawa T, Nakamura K:
Single local injection of recombinant fibroblast
growth factor-2 stimulates healing of segmental bone
defects in rabbits. J Orthop Res 16: 654-659, 1998
5. Okazaki H, Kurokawa T, Nakamura K, Matsushita T,
Mamada K, Kawaguchi H: Stimulation of bone formation by recombinant fibroblast growth factor-2 incallotasis bone lengthening of rabbits. Calcif Tissue
Int 64: 542-546, 1999
6. Nakamura I, Ikegawa S, Okawa A, Okuda S,
Koshizuka Y, Kawaguchi H, Nakamura K, Koyama T,
Goto S, Toguchida J, Matsushita M, Ochi T, Takaoka
K, Nakamura Y. Association of the human NPPS
gene with ossification of the posterior longitudinal
ligament of the spine (OPLL). Hum Genet 104: 492497, 1999
7. Manabe N, Oda H, Nakamura K, Kuga Y, Uchida S,
Kawaguchi H: Involvement of fibroblast growth factor-2 in joint destruction of rheumatoid arthritis
patients. Rheumatology 38: 714-720, 1999
8. Takayanagi H, Juji T, Miyazaki T, Iizuka H,
Takahashi T, Isshiki M, Okada M, Tanaka Y,
Koshihara Y, Oda H, Kurokawa T, Nakamura K,
Tanaka S: Suppression of arthritic bone destruction
by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest 104: 137-146,
1999
9. Kawaguchi H, Manabe N, Miyaura C, Chikuda H,
Nakamura K, Kuro-o M: Independent impairment of
osteoblast and osteoclast differentiation in klotho
mouse exhibiting low-turnover osteopenia. J Clin
Invest 104: 229-237, 1999
10. Nishikawa T, Ogawa S, Kogita K, Manabe N,
Katsumata T, Nakamura K, Kawaguchi H: Additiveeffects of combined treatment with etidronate andalfacalcidol on bone mass and mechanical properties
in ovariectomized rats. Bone 27: 647-654, 2000
11. Takayanagi H, Iizuka H, Juji T, Nakagawa T,
Yamamoto A, Miyazaki T, Koshihara Y, Oda H,
Nakamura K, Tanaka S: Involvement of receptor activator of nuclear factor kB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes268

in rheumatoid arthritis. Arthritis Rheum 43: 259269, 2000
12. Kawaguchi H, Chikazu D, Nakamura K, Kumegawa
M, Hakeda Y: Direct and indirect actions of fibroblast growth factor-2 on osteoclastic bone resorption
in cultures. J Bone Miner Res 15: 466-473, 2000
13. Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K,
Azuma Y, Ohta T, Kadowaki T, Nakamura K,
Kawaguchi H: Insulin receptor substrate-1 inosteoblast is indispensable for maintaining boneturnover. J Clin Invest 105: 935-943, 2000
14. Takayanagi H, Ogasawara K, Hida S, Chiba T,
Murata S, Sato K, Takaoka A, Yokochi T, Oda H,
Tanaka K, Nakamura K, Taniguchi T: T cell-mediatedregulation of osteoclastogenesis by signaling crosstalk between RANKL and IFN-γ. Nature 40: 600605, 2000
15. Nakagawa T, Tanaka S, Suzuki T, Takayanagi H,
Miyazaki T, Nakamura K. Tsuruo T: Overexpressionof the csk gene suppresses tumor metastasis in vivo.
Int J Cancer 88: 384-391, 2000
16. Miyazaki T, Takayanagi H, Isshiki M, Takahashi T,
Okada M, Fukui Y, Oda H, Nakamura K, Hirai H,
Kurokawa T, Tanaka S: In vitro and in vivo suppression of osteoclast function by adenovirus vectorinduced csk gene. J Bone Miner Res 15: 41-51, 2000
17. Miyazaki T, Katagiri H, Kanegae Y, Takayanagi H,
Sawada Y, Yamamoto A, Pando MP, Asano T, Verma
IM, Oda H, Nakamura K, Tanaka S: Reciprocal role of
ERK and NF-κB pathways in survival and activationof osteoclasts. J Cell Biol 148: 333-342, 2000
18. Miura T, Tanaka S, Seichi A, Arai M, Goto T, Katagiri
H, Asano T, Oda H, Nakamura K: Partial functional
recovery of paraplegic rat by adenovirus-mediatedgene delivery of constitutively active MEK1. Exp
Neurol 166: 115-126, 2000
19. Kawaguchi H, Manabe N, Chikuda H, Nakamura K,
Kuro-o K: Cellular and molecular mechanism of lowturnover osteopenia in the klotho-deficient mouse.
Cell Mol Life Sci 57: 731-737, 2000
20. Ohtsuka T, Ohnishi I, Nakamura K, Takamoto S:
New instrumentation for video-assisted anterior
spine release. Surg Endosc 14: 682-684, 2000
21. Manabe N, Kawaguchi H, Chikuda H, Miyaura C,
Inada M, Nagai R, Nabeshima Y, Nakamura K,
Sinclair AM, Scheuermann RH, Kuro-o M:
Connection between B lymphocyte and osteoclastdifferentiation pathways. J Immunol 167: 2625-31,
2001
22. Yamamoto N, Yamamoto S, Inagaki F, Kawaichi M,
Fukamizu A, Kishi N, Matsuno K, Nakamura K,
Weinmaster G, Okano H, Nakafuku M: Role ofDeltex-1 as a transcriptional regulator downstreamof the Notch receptor. J Biol Chem 276: 45031-45040,
2001
23. Yamamoto S, Nagano M, Sugimori M, Kosako H,
Nakatomi H, Yamamoto N, Takebayashi H,
Nabeshima Y, Kitamura T, Weinmaster G, Nakamura
K, Nakafuku M: Transcription factor expression andNotch-dependent regulation of neural progenitors inthe adult rat spinal cord. J Neurosci 21: 9814-9823,
2001
24. Yamamoto S, Yamamoto N, Kitamura T, Nakamura
K, Nakafuku M: Proliferation of parenchymal neuralprogenitors in response to injury in the adult rat
spinal cord. Exp Neurol 172: 115-127, 2001
25. Ikeda T, Mabuchi A, Fukuda A, Hiraoka H,
Kawakami A, Yamamoto S, Machida H, Takatori Y,
Kawaguchi H, Nakamura K, Ikegawa S: Identificationof sequence polymorphisms in two sulfation-related
genes, PAPSS2 and SLC26A2, and an association
analysis with knee osteoarthritis. J Hum Genet 46:
538-543, 2001
26. Kawaguchi H, Nakamura K, Tabata Y, Ikada Y,
Aoyama I, Anzai J, Nakamura T, Hiyama Y, Tamura
M: Acceleration of fracture healing in non-humanprimates by fibroblast growth factor-2. J Clin
Endocrinol Metab 86: 875-880, 2001
27. Koshizuka Y, Ikegawa S, Sano M, Nakamura K,
Nakamura Y: Isolation of novel mouse genes associated with ectopic ossification by differential display
method using ttw, a mouse model for ectopic ossification. Cytogenet Cell Genet 94: 163-168, 2001
28. Seichi A, Takeshita K, Ohnishi I, Kawaguchi H,
Akune T, Anamizu Y, Kitagawa T, Nakamura K:
Long-term results of double-door laminoplasty forcervical stenotic myelopathy. Spine 26: 479-487,
2001
29. Ogata N, Shiraki M, Koshizuka Y, Nakamura K,
Kawaguchi H: A polymorphic variant at the Wernerhelicase (WRN) gene is associated with bone density,
but not spondylosis, in postmenopausal women. J
Bone Miner Metab19: 296-301, 2001
30. Nakajima S, Nakamura K, Masamura K, Sakuma I,
Dohi T: Three-dimensional medical imaging display
with computer-generated integral photography.
Comput Med Imaging Graph 25: 235-241, 2001
31. Nakajima S, Nakamura K, Masamura K, Sakuma I,
Dohi T: Development of a tracking method for image
analysis of time-lapse deformation of trabecular
structure in a human bone. Comput Med Imaging
Graph 25: 443-448, 2001
32. Koshizuka Y, Ikegawa S, Sano M, Nakamura K,
Nakamura Y: Isolation, characterization, and mapping of the mouse and human WDR8 genes, members of a novel WD-repeat gene family. Genomics 72:
252-259, 2001
33. Nishimura G, Manabe N, Kosaki K, Haga N, Ohashi
H, Nakamura K, Ikegawa S: Spondylar dysplasia in
Type X collagenopathy. Pediatr Radiol 31: 76-80,
2001
34. Akune T, Ogata N, Seichi A, Ohnishi I, Nakamura K,
Kawaguchi H: Insulin secretory response is positively
associated with the extent of ossification of the posterior longitudinal ligament of the spine. J Bone Joint
Surg Am 83-A: 1537-1544, 2001
35. Mabuchi A, Ikeda T, Fukuda A, Koshizuka Y,
Hiraoka H, Miyoshi K, Haga N, Kawaguchi H,
Kawakami A, Yamamoto S, Takatori Y, Nakamura K,
Ikegawa S: Identification of sequence polymor-

phisms of the COMP (cartilage oligomeric matrix
protein) gene and association study in osteoarthrosisof the knee and hip joints. J Hum Genet 46: 456-462,
2001
36. Mabuchi A, Haga N, Ikeda T, Manabe N, Ohashi H,
Takatori Y, Nakamura K, Ikegawa S: Novel mutationin exon 18 of the cartilage oligomeric matrix protein
gene causes a severe pseudoachondroplasia. Am J
Med Genet 104: 135-139, 2001
37. Fukui N, Nakajima K, Tashiro T, Oda H, Nakamura
K: Neutralization of fibroblast growth factor-2
reduces intraarticular adhesions. Clin Orthop 383:
250-258, 2001
38. Fukui N, Fukuda A, Kojima K, Nakajima K, Oda H,
Nakamura K: Suppression of fibrous adhesion byproteoglycan decorin. J Orthop Res 19: 456-462, 2001
39. Ikeda T, Mabuchi A, Fukuda A, Kawakami A,
Yamada R, Yamamoto S, Miyoshi K, Haga Y, Hiraoka
H, Takatori Y, Kawaguchi H, Nakamura K, Ikegawa
S: Association analysis of single nucleotide polymorphisms in cartilage-specific collagen genes with knee
and hip osteoarthritis in the Japanese population. J
Bone Miner Res 17: 1290-1296, 2002.
40. Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H,
Miura T, Nishina H, Katada T, Wakabayashi K, Oda
H, Nakamura K, Tanaka S: Possible involvement of
IkB kinase 2 and MKK7 in osteoclastgenesis induced
by receptor activator of nuclear factor kB ligand. J
Bone Miner Res 17: 612-621, 2002
41. Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T,
Sato K, Yokochi T, Oda H, Nakamura K, Ida N,
Wagner EF, Taniguchi T: RANKL maintains bonehomeostasis through c-Fos-dependent induction ofinterferon-β. Nature 416: 744-749, 2002
42. Matsuda K, Yoshida K, Taya Y, Nakamura K,
Nakamura Y, Arakawa H: p53AIP1 regulates the
mitochondrial apoptotic pathway. Cancer Res 62:
2883-2889, 2002
43. Koshizuka Y, Kawaguchi H, Ogata N, Ikeda T,
Mabuchi A, Seichi A, Nakamura Y, Nakamura K,
Ikegawa S: Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine. J Bone Miner
Res 17: 138-144, 2002
44. Shimoaka T, Ogasawara T, Yonamine A, Chikazu D,
Hirotaka H, Nakamura K, Itoh N, Kawaguchi H:
Regulation of osteoblast, chondrocyte, and osteoclast
functions by fibroblast growth factor (FGF)-18 incomparison with FGF-2 and FGF-10. J Biol Chem
277: 7493-7500, 2002
45. Ogata N, Matsumura Y, Shiraki M, Kawano K,
Koshizuka Y, Hosoi T, Nakamura K, Kuro-o M,
Kawaguchi H: Association of klotho gene polymorphism with bone density and spondylosis of thelumbar spine in postmenopausal women. Bone 31:
37-42, 2002
46. Ogata N, Koshizuka Y, Miura T, Iwasaki M, Hosoi T,
Shiraki M, Seichi A, Nakamura K, Kawaguchi H:
Association of bone metabolism regulatory factor
gene polymorphisms with susceptibility to ossifica-269

tion of the posterior longitudinal ligament of thespine and its severity. Spine. 27: 1765-1771, 2002
47. Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P,
Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H,
Inoue S, Nabeshima Y, Nakamura K, Kuro-o M,
Kawaguchi H: Klotho gene polymorphisms associated with bone density of aged postmenopausal
women. J Bone Miner Res (in press)
48. Ikeda T, Junwei Z, Chano T, Mabuchi A, Fukuda A,
Kawaguchi H, Nakamura K, Ikegawa S: Identificationand characterization of the human long form of Sox5
(L-SOX5) gene. Gene (in press)
49. Kotani H, Kawaguchi H, Ueno S, Shimoaka T,
Iwasaka M, Ozawa H, Nakamura K, Hoshi K: Strong
static magnetic field stimulates bone formation to adefinite orientation in vitro and in vivo. J Bone Miner
Res (in press)
50. Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y,
Tobe K, Takagi H, Azuma Y, Kadowaki T, Nakamura
K, Kawaguchi H: Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol (in press)

270

Department ofOphthalmology
Outline and Research Objectives
The Department of Ophthalmology University of Tokyo was established in 1889. Since
then, over a century, our department has played a crucial role as a pioneer in every aspects
of ophthalmology in Japan and delivered a lot of international leaders in both clinical andresearch fields of ophthalmology. The chairman Jujiro Komoto (1889-1922) introduced
Western ophthalmology into Japan and established the basics in Japanese ophthalmologic
society. The chairman Shinobu Ishihara (1922-1940) developed Ishihara test plate for color
blindness, which is still a world-wide golden standard as a screening examination for color
blindness. The chairman Yoshiharu Shoji (1940-1949) investigated on the pathogenesis of
cataract and the chairman Hagiwara (1915-1964) conducted basic and clinical research on
Behcet’s disease, the cornea, and the extra-ocular muscles. The chairman Shinichi Shikano(1964-1971) performed research on Behcet’s disease and autonomic nervous system in theeye. The chairman Saiichi Mishima (1971-1987) controlled comprehensive research on thephysiology of the cornea, ocular pharmacology, and surgical biology, and served as a chieforganizer of international congress of ophthalmology held in Kyoto in 1978. The chairman
Kanjiro Masuda (1987-1997) conducted research on the pathogenesis and therapy of uveitis.
The chairman Makoto Araie (1997-present) has organized thorough research on ocular pharmacology, ocular blood-flow, and clinical and basic aspects of glaucoma and cornea transplantation.

Faculties and Students:
Professor and Chair
Associate Professor

Makoto Araie, MD., Ph.D. (1997~)
Hidetoshi Kawashima, MD., Ph.D.
Goji Tomita, MD., Ph.D.
Lecturer
Yasuyuki Suzuki, MD., Ph.D.
Yasuhiro Tamaki, MD., Ph.D.
Satoru Kato, MD., Ph.D.
Miyuki Nagahara, MD., Ph.D.
Associate ...............................10
Postdoctoral Fellow ................1
Secretary .................................2

Past Researches and Major accomplishments
1) Evaluation of important parameters of ocularphysiology by means of in vivo fluorophotometry
or in vivo measurements of protein concentrationin the aqueous humor:
Effects of various anti-glaucoma eye drops on boththe aqueous flow rate and blood-aqueous-barrier(BAB) permeability were first and quantitatively determined in human eyes and anti−inflammatory effects
of topical NSAID were first quantitatively determinedin patients undergoing cataract surgery. Further, amethod to non-invasively monitor the aqueous production reducing effects of anti−glaucoma drugs inhuman eyes or toxic effects of intra-ocular irrigating

solution in animal eyes have been first developed.
The techniques thus establish were used in developing a new anti-glaucoma drug, which is now marketed.

2) Study of cornea:
Permeability to the cornea is the rate-limiting factor for intra-ocular penetration of topically instilled
drugs. A pre-existing method for in vivo determination of corneal endothelial (CE) permeability was
improved so that status of its harrier function can be
estimated more systematically. A new in-vitro
method for quantitative evaluation of CE permeability
was established, which was world-wide used for comparing safety of various intra-ocular irrigating solutions, and the lowest Ca 2+ concentration needed tomaintain the CE integrity was first determined.
Further, molecular biological features of corneal
endothelial cells were investigated and the above
studies are followed by the present investigation ofregenerative medicine of corneal graft for corneal
transplantation.
3) Study of ocular pharmacokinetics:
Using the 2-compartment computer model, ocularpharmacokinetics of topically instilled beta-blockers,
one of the most important anti-glaucoma drug, werestudied and binding of topically instilled beta-blockers
to uveal pigment and its clinical implication were first271

demonstrated. Trans-corneal and intravitreal kineticsof flourophores were studied to determine factors tofacilitate intra-ocular penetration of topically instilled
and systemically administered drugs.

4) Clinical study of glaucoma:
Glaucoma is the leading cause of blindness indeveloped countries and open angle glaucoma represents 75% of all glaucomas in Japan. Surgical techniques of glaucoma were improved by introducing
antimetabolites and basic features of adjunctive use ofanti metabolites investigated. By computer analysis ofvisual field results, IOP-dependent damages in thevisual field were elucidated, optimal sectorization oftest points determined and it was also found that IOP
is a risk factor for progression also in normal tension
glaucoma. And, effects of glaucoma surgery or calcium
antagonists on the visual field progression in normal
tension glaucoma were first qualitatively determined.
New image analysis techniques, psychophysical methods and new anti− glaucoma eye drops were evaluated and one anti−glaucoma eye drop could be successfully developed and marketed.
5) Basic study of glaucoma:
Clinical study of glaucoma demonstrated that IOP
is not the only factor contributing to progression ofglaucoma, which lead to experimental studies on neuroprotection. Conditioned medium from human amniotic epithelial cells was first found to have neurotrophic effects on cultured neurons including retinal
ganglion cells (RGCS) and interaction between retinal
glial cells or NO and isolated RGCs were determined.
Novel gene mutation in Japanese glaucoma patientswas found and MYOC, one of glaucoma genes, wascloned in the bovine eye.
6) Study of ocular blood flow:
Clinical studies of glaucoma revealed that local circulation is also involved in progression of glaucoma.
Apparatuses which can non-invasively estimate theblood flow in the iris, retina, choroids or optic nerve
head utilizing laser speckle phenomenon in livingeyes were constructed, establishing the laser speckle
method as an in-vivo, non-invasive peripheral bloodflow measurement method which can be applied inhuman subjects. Using this method, effects of calcium
antagonists, topical eye drops or surgical procedureson ocular circulation of various ocular tissues could befirst systemically studied. It was first found that theocular tissue most effectively affected is different
depending on the Ca2+-antagonist used (nicardipine
selectively affects choroidal circulation, lomerizine
ONH circulation etc). The important new finding
obtained by the ocular blood studies was, topicallyinstilled drugs can influence the circulation in the pos-272

terior parts of the eye through their direct penetration
to the posterior part of the eye, which have been considered to be impossible. This finding not only has
great clinical implication in ocular therapeutics, butalso prompted the current study to confirm that topically instilled drugs penetrate to the posterior retina,
choroids or retrobulbar tissues at pharmacologicalconcentrations.

Current Researches and Future Prospects.
1) Study of Cornea:
To cope with very limited supply of donor corneas
and allograft rejection in corneal transplantation, thereconstruction of artificial cornea has been attemptedusing the tissue engineering technology. A method to
culture human corneal endothelial cells (HCEC) has
been first established and, using cultured HCFCs andhuman corneal stroma the cornea could be successfully reconstructed. Thus reconstructed cornea has 7080% of cell density, pump function and barrier function of normal HCECs. The reconstructed cornea
transplanted to rabbit eye stayed transparent during
postoperative 6 months, showing transplanted HCEC
normally functioning. Animal corneal stroma as a carrier of cultured HCECs is being investigated. The
cornea reconstructed with porcine corneal stroma and
HCECs showed average cell density pump function of
about 60-70% of normal HCECs and bone marrowcells injected into rat anterior chamber were found totransform into CE-like cells, suggesting that self
immature cells can transform into CEs. Possibility ofutilizing cultured HCEC from fetus is now investigated. Antigen-specific T cell activation is a critical stepin the rejection of transplanted allografts. To activate
T cells, two kinds of signal are necessary: signal mediated by T cell receptor (TCR)/CD3 complex and the costimulatory signal by cell surface adhesion molecules
such as CD80/86 and ICAM-1. As novel therapies forrejection after corneal transplantation, the feasibilityof anti-CD80/86 antibodies is being investigated using
murine corneal transplantation model with a complete mismatch at major and minor histocompatibility. Clinical usage of reconstructed cornea, first in highrisk corneal transplantation cases, is planned in 5
years, to resolve very limited supply of donor corneas
in Japan. By incorporating gene technology, grafts
much better functioning with much less chance to be
rejected than the donor cornea may be constructed.
To reduce allograft rejection, therapy with anti-CD
80/86 antibodies and chemokine receptor antagonist
such as CCRI antagonist, which is also involved in
induction of rejection, may be also possible.

2) Study of ocular pharmacokinetics:
Our new finding suggesting penetration of topically instilled drug to the posterior parts of the eye at
pharmacological concentrations will be a breakthrough in medical treatment of diseases of posterior
parts of the eye such as the retinal, choroidal or optic
nerve disorders. Whole-head autoradiography and a
new method of isolation of posterior ocular tissues are
now being carried out and confirmed the above findings. Factors and routes contributing to the posterior
penetration of instilled drugs will be elucidated, andsystemically safe, local treatment of retinal, choroidal
or optic nerve disorders is to be developed.
3) Clinical study of glaucoma:
As one of the three chief investigators, Makoto
Araie conducted an epidemiological study of glaucoma
and related ocular diseases in Tajimi area and now isanalyzing the obtained results as a chief of data analysis committee. This is the first ophthalmological epidemiological study carried out in mongoloids and its
result will have a great impact in the field of ophthalmology. Several longitudinal, some of them randomized and prospective, studies are being conducted by
Makoto Araie as a chief investigator a) A 3−yearprospective, randomized，multi-centered and comparative study of nipradilol and timolol on the progression of normal tension glaucoma. The result of
this study will first elucidate if non-IOP dependentrisk factors of glaucoma can be treated by topicaldrugs or not, and if a positive result is obtained, it will
be a great break-through in the medical treatment ofglaucoma. b) The multi-centered, randomized, placebo-controlled study on the effects lomerizine, a Ca 2+blocker, on the retinal blood flow is the first to study
if retinal blood flow can be selectively increased bysystemically safe oral Ca2+-antagonis, lomerizine, andif a positive result is obtained, it will be a breakthrough in the medical treatment of retinal diseases.
Other longitudinal or cross-sectional studies now
ongoing includes disk bleeding study to investigate
whether myopic-type disc is associated less disc
bleeding but more progression of damage as compared with non-myopic type disc, advanced stage
glaucoma study where disability in daily life in thelate stage of the disease is prospectively questioned,
frequency doubling technology visual field study
where this new psychophysical test is prospectively
evaluated from view point of early detection of glaucoma progression and scanning laser ophthalmoscopy
study where morphometry of the optic disc inJapanese patients is quantitatively estimated on multicenter-based protocol, development of visual disability questionnaire designed to evaluate visual disability
in Japanese glaucoma patients who vertically read andwrite, analysis of filtering bleb characteristics after

trabeculectomy in Japanese patients to find contributing factors to the late stage bleb-related complications,the most vision-threatening complication of glaucoma
surgery. The result obtained from the above studies infuture will shed new light on the diagnosis, follow-up,
treatment and rehabilitation of glaucoma, the second
leading cause of blindness in Japan, of which prevalence in adults was found to be as high as 5% (unpublished result of the above mentioned Tajimi Study).

4) Basic study of glaucoma:
Makoto Araie is serving as a chairman of
Glaucoma Optic Neuropathy Study Group and established monkey glaucoma model is used to study how
glaucomatous damaging processes impair the optic
nerve head (ONH) structure, ONH circulation andneural functions (visual field, receptor field of neurons
in lateral geniculate body, etc) and how the potential
drugs can modify them, which is impossible to study
in humans. ONH is the tissue primarily involved inglaucomatous damage and ONH damage results inloss of retinal ganglion cells in retina. Using established system of culture of isolated retinal ganglion
cells and isolated Müller cells, factors, affecting survival of these cells, including therapeutic agents, are
now intensively studied. Mammalian retina is composed of seven major cell types, Müller glia, and six
neural cell types, retinal ganglion cell (RGC), bipolarcell, horizontal cell, amacrine cell, rod and cone photoreceptor cell. Unlike amphibian or fish, adult mammalian retina has been considered to be devoid ofstem or progenitor cells and that substantial regeneration dose not take place.
However, a recent study has unexpectedly demonstrated the presence of retinal stem cells in adultmice, suggesting the possibility that these cells can beutilized as a potential cell source of transplantation
therapy for damaged retinal cells including RGCs.
Animal model is pre-requisite for the realization of thetransplantation therapy, and rabbit is one of the mostsuitable animals because of its relatively large-sized
eyes, easiness in handling and reasonable price.
Method to isolate retinal stem cells from ciliary
epithelium using neurosphere-forming assay has been
established not only in mice but also rabbits andmonkeys. Ongoing studies address factors involved indifferentiation of retinal stem cells and how thesecells can be utilized as cell source of transplantation
therapy of retinal degenerative disorders including
glaucoma. In culturing isolated RGCs and retinal stem
cells, and in providing substrate for transplantation,
human amniotic epithelial cells and our experience onthem should be of considerable use.
5) Study of Ocular blood flow:
In addition to the laser speckle method that were273

already developed for non-invasive measurement of
peripheral blood flow in ocular tissues, an apparatus
for Color Doppler Imaging and that for Laser Doppler
Velocimetry have been recently introduced. The former measures the absolute blood velocity of vessels in
the orbit (diameter > 100µ) and the latter that of large
retinal vessels (diameter ≒100µ). Our laboratory is
the only one in the world that equipped with theabove 3 apparatuses and using 3 apparatuses, physiology, pathology and pharmacology of ocular circulationfrom feeding vessels to peripheral circulation can be
first systematically investigated. The subjects of the
on-going studies are: Measurement of peripheral
resistance in normal subjects with genetically highrisk for systemic hypertension; Change in autoregulatory capacity of retinal and ONH circulation withaging, development of glaucoma or development ofdiabetic retinopathy; and Assessment of hemodynamic parameters most correctly and sensitively reflecting
status of peripheral vascular bed. The results obtainedby above studies will shed light not only on further
understanding of pathophysiology of systemic hypertension and ocular disorders associated with circulatory abnormalities, but also lead to establishment of
hemodynamic parameters most sensitively reflecting
therapeutic effects of various drugs on retinal or ONH
disorders including glaucoma.

Research Grants
Grant-in-aid for scientific research from Ministryof Education, Culture, Sports, Science andTechnology:
1. Tenkai-Kenkyu (A)2, No.10357016, 1998-1999:| Chief
investigator, ¥19,500,000274

2. Kiban-Kenkyu (A)1, No. 11307036, 1999-2001: Chief
investigator, ¥41,010,000
3. Kiban-Kenkyu (B)2, No. 12557146, 2000-2001: Chief
investigator, ¥19,700,000
4. Kiban-Kenkyu (A)1, No. 14207069, 2002-2004: Chief
investigator, ¥49,998,000

Grant-in-aid for scientific research from Ministryof Health, Labour and Welfare. H-10-Sensory Organ-005, 1998-2000: Chief investigator, ¥73,500,000

Select Publications
1. Makoto ARAIE, Masahiro TAKASE, Yasuo SAKAI,
Yukihisa ISHII, Yukio YOKOYAMA & Masatoshi
KITAGAWA: Beta-adrenergic blockers: ocular penetration and binding to the uveal pigment. Japanese
Journal of Ophthalmology 26:248-263, 1982
2. Makoto ARAIE: A Reevaluation of corneal endothelial permeability to fluorescein. Experimental Eye
Research 41: 383-390, 1985
3. Makoto ARAIE: Barrier function of the corneal
endothelium and intraocular irrigating solutions.
Archives of Ophthalmology, 104;435-438, 1986
4. Makoto ARAIE & David M MAURICE: The rate ofdiffusion of fluorophores through the corneal epithelium and stroma. Experimental Eye Research 44: 7387, 1987
5. Chihiro SETO, Makoto ARAIE, Mitsuru SAWA, &Masahiro TAKASE: Human corneal endothelial permeability to fluorescein and fluorescein glucuronide.
Investigative Ophthalmology & Visual Science 28:1457-1463, 1987
6. Makoto ARAIE, Eiichi SHIRASAWA & Koji HIKITA:
Effects of oxidized glutathione on the barrier function of the corneal endothelium. InvestigativeOphthalmology & Visual Science 29: 1884-1887,
1988
7. Masami KONDO & Makoto ARAIE: Concentration
change of 5-fluorouracil in the external segment of
the eye after subconjunctival injection. Archives ofOphthalmology, 106: 1718-1721, 1988
8. Masami KONDO & Makoto ARAIE: Iontophoresis of
5-fluorouracil into the conjunctiva and sclera.
Investigative Ophthalmology & Visual Science 30:
583-585, 1989
9. Tetsuro OSHIKA & Makoto ARAIE: Time course ofchanges in aqueous protein concentration and flowrate after oral acetazolamide. Investigative
Ophthalmology & Visual Science 31: 527-534, 1990
10. Makoto ARAIE, Eiichi SHIRASAWA & TokieOHHASHI: Intraocular irrigating solutions and permeability of the blood-aqueous barrier. Archives ofOphthalmology, 108: 882-885, 1990
11. Makoto ARAIE, Koichi HAMANO, Shuichiro
EGUCHI & Shun MATSUMOTO: Effect of calcium
ion concentration of the permeability of the corneal
endothelium. Investigative Ophthalmology & Visual
Science 31:2191-2193, 1990
12. Makoto ARAIE & David M Maurice: The loss of fluorescein, fluorescein glucuronide and FITC-dextran
from the vitreous by the anterior and retinal pathways. Experimental Eye Research 52: 27-39, 1991
13. Mikiro MORI & Makoto ARAIE: A simple method ofdetermining the time course of timolol’s effects on
aqueous flow in humans. Archives ofOphthalmology 109: 1099-1103, 1991
14. Tetsuro OSHIKA, Makoto ARAIE, Tetsuya SUGIYAMA, Masayuki NAKAJIMA & Ikuo AZUMA: Effect ofbunazosin hydrochloride on intraocular pressure andaqueous humor dynamics in normotensive humaneyes. Archives of Ophthalmology 109: 1569-1574,
1991
15. Mikiro MORI, Makoto ARAIE, Masahiro SKURAI &Tetsuro OSHIKA: Effects of pilocarpine and tropicamide on blood-aqueous barrier permeability inman. Investigative Ophthalmology & Visual Science
33: 416-423, 1992
16. Yasuyuki SUZUKI, Makoto ARAIE & Yazuo OHASHI:
Sectorization of central 30∞ visual field in glaucoma.
Ophthalmology 100: 69-75, 1993
17. Satoshi KOYANO, Makoto ARAIE & Shuichiro
EGUCHI: Movement of fluorescein and its glucuronide across retinal pigment epithelium-choroid.
Investigative Ophthalmology & Visual Science 34:
531-583, 1993
18. Junkichi YAMAGAMI, Makoto ARAIE, Makoto
AIHARA & Seiichiro YAMAMOTO: Diurnal variation
in intraocular pressure of normal-tension glaucoma
eyes. Ophthalmology 100: 643-650, 1993
19. Makoto ARAIE, Junkichi YAMAGAMI & Yasuyuki
SUZUKI: Visual field defects in normal-and high-tension glaucomas. Ophthalmology 100: 1808-1814,
1993
20. Makoto ARAIE & Kiyoshi ISHII: Effects of apraclonidine on intraocular pressure and blood-aqueous bar-rier permeability after phacoemulsification andintraocular lens implantation. American Journal of
Ophthalmology 116: 67-71, 1993
21. Makoto ARAIE, Maki SEKINE, Yasuyuki SUZUKI &Nobuyuki KOSEKI: Factors contributing to the progression of visual field damage in eyes with normaltension glaucoma. Ophthalmology 101: 1440-1444,
1994
22. Yasuhiro TAMAKI, Makoto ARAIE, Eizo KAWAMOTO, Shuichiro EGUCHI & Hitoshi FUJII: Noncontact,
two-dimensional measurement of retinal microcirculation using laser speckle phenomenon. Investigative
Ophthalmology & Visual Science 35: 3825-3834,
1994
23. Yasuhiro TAMAKI, Makoto ARAIE, Eizo KAWAMOTO, Shuichiro EGUCHI & Hitoshi FUJITA: Non-contact, two-dimensional measurement of tissue circulation in choroid and optic nerve head using laser
speckle phenomenon. Experimental Eye Research 60:
373-384, 1995
24. Minoru KIMURA, Makoto ARAIE & Satoru KOYANO: Movement of carboxyfluorescein across retinal
pigment epithelium-choroid. Experimental Eye
Research 63: 51-56, 1996
25. Hiromu K MISHIMA, Kanjiro MASUDA, Yoshiaki
KITAZAWA, Ikuo AZUMA & Makoto ARAIE: A
comparison of latanoprost and timolol in primary
open-angle glaucoma and ocular hypertension. A 12week study. Archives of Ophthalmology 114: 929932, 1996
26. Nobuyuki KOSEKI, Makoto ARAIE, Shiroaki SHIRATO & Seiichiro YAMAMOTO: Effect of trabeculectomy on visual field performance in central 30∞ visual
field in progressive normal tension glaucoma.
Ophthalmology 104: 197-201;1997
27. Makoto ARAIE, Mariko KITAZAWA & Nobuyuki
KOSEKI : Intraocular pressure and central visual fieldof normal tension glaucoma. British Journal of
Ophthalmology 81:852-856,1997
28. Makoto ARAIE & Minoru KIMURA: Intraocular irrigating solutions and barrier function of retinal pigment epithelium. British Journal of Ophthalmology
81: 150-153;1997
29. Mikiko KANNO, Makoto ARAIE, Ken TOMITA &Kimio SAWANOBORI. Effects of topical nipradilol, aβ- blocking agent with α-blocking and nitroglycerin-like activities, on aqueous humor dynamics andfundus circulation. Investigative Ophthalmology &Visual Science 39:736-743,1998
30. Atsuo TOMIDOKORO, Makoto ARAIE, Yasuhiro
TAMAKI & Ken TOMITA. In vivo measurement of
iridial circulation using laser speckle phenomenon.
Investigative Ophthalmology & Visual Science
39:364-371,1998
31. Nobuyuki KOSEKI, Makoto ARAIE, Junkichi YAMAGAMI, Shiroaki SHIRATO & Seiichiro YAMAMOTO. Effect of oral brovincamine on visual field damage in normal tension glaucoma with low-normalpressure. Journal of Glaucoma 8:117-123,1999

275

32. Ken TOMITA, Makoto ARAIE, Yasuhiro TAMAKI,
Miyuki NAGAHARA & Tetuya SUGIYAMA. Effectsof nilvadipine, a calcium antagonist, on rabbit ocular
circulation and optic never head circulation in normal tension glaucoma subjects. Investigative
Ophthalmology & Visual Science. 40: 11441151,1999
33. Yasuhiro TAMAKI, Makoto ARAIE, Miyuki NAGAHARA & Ken TOMITA. Acute effects of cigarettesmoking on tissue circulation in human optic nerve
head and choroid-retina. Ophthalmolgy 106:564569,1999
34. Mikiko KANNO, Makoto ARAIE, Hiroshi KOIBUCHI& Kanjirou MASUDA. Effects of topical nipradilol, aβ-blocking agent with α-blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans. British Journal of
Ophthalmology 84:293-299, 2000
35. Yuichi KAJI, Tomohiko USUI, Tetsuro OSHIKA,
Masao MATUBARA, Hidetoshi YAMASHITA,
Makoto ARAIE, Toshinori MURATA, Tetsuro
ISHIBASHI, Ryoji NAGAI, Seikoh HORIUCHI &Shiro AMANO. Advanced Glycation end products indiabetic corneas. Investigative Ophthalmology &Visual Science 41:362-368, 2000
36. Fumiko TANIGUCHI, Yasuyuki SUZUKI, Hiroki
KURIHARA, Yukiko KURIHARA, Hiroyoshi KASAI,
Shiroaki SHIRATO & Makoto ARAIE. Molecularcloning of the bovine MYOC and induction of its
expression in trabecular meshwork cells.
Investigative Ophthalmology & Visual Science
41:2070-2075, 2000
37. Kenji INOUE, Shunichiro KUBOTA, Tadahiko
TSURU, Makoto ARAIE & Yousuke SEYAMA.
Cholestanol induces apoptosis of corneal endothelial
and lens epithelial cells. Investigative
Ophthalmology & Visual Science 41:991-997, 2000
38. Tomohiko USUI, Shiro AMINO, Kaori SUZUKI,
Kazunori MIYATA, Makoto ARAIE, Paraskevi
HELDIN & Hidetoshi YAMASHITA. Expression andregulation of hyaluronan synthase in corneal
cndothelial cells. Investigative Ophthalmology &Visual Science 41:3261-3267, 2000
39. Saiko UCHIDA, Yukiko INANAGA, Makiko
KOBAYASHI, Shoei HURUKAWA, Makoto ARAIE &Norio SAKURAGAWA. Neurotrophic function of
conditioned medium from human amniotic epithelial
cells. J Neuroscience Research 62:585-590, 2000
40. Yasuhiro TAMAKI, Makoto ARAIE, Tomohiko
HASEGAWA & Miyuki NAGAHARA. Optic nerve
head circulation after intraocular pressure reduction
achieved by trabeculectomy. Ophthalmology 108:627-632, 2001
41. Ken MIZUNO, Takashi KOIDE, Mitsuo YOSHIMURA& Makoto ARAIE. Neuroprotective effect andintraocular penetration of nipradilol, a beta-blocker
with nitric oxide donative action. Investigative
Ophthalmology & Visual Science 42:688-694, 2001
42. Tomohiko USUI, Masumi HARA, Hiroaki SATOH,
Nobuo MORIYAMA, Humie KAGAYA, Shiro

276

AMANO, Tetsuro OSHIKA, Yasuo ISHII, Nobuhiro
IBARAKI, Chiaki HARA, Motoei KUNIMI, Eisei
Noiri, Kazuhisa TSUKAMOTO, Jun INATOMI,
Hayato KAWAKAMI, Hitoshi ENDOU, Takashi
IGARASHI, Astuo GOTO, Toshiro FUJITA, Makoto
ARAIE, George SEKI. Molecular basis of ocularabnormalities associated with proximal renal tubularacidosis. Journal of Clinical Investigation
2001;108:107-115
43. Yukihiko MASHIMA, Yasuyuki SUZUKI, Yuri
SERGEEV, Yuichiro OHTAKE, Tomihiko TANINO,
Itaru KIMURA, Hiroshi MIYATA, Makoto AIHARA,
Hidenobu TANIHARA, Masaru INATANI, Noriyuki
AZUMA, Takeshi IWATA, Makoto ARAIE. Novelcytochrome P4501B1(CYP1B1) gene mutations inJapanese patients with primary congenital glaucoma.
Investigative Ophthalmology & Visual Science
2001;42: 2211-2216
44. Kenji KASHIWAGI, Yoko IIZUKA, Makoto ARAIE,
Yasuyuki SUZUKI, Shigeo TSUKAHARA. Effects ofretinal glial cells on isolated rat retinal ganglion cells.
Investigative Ophthalmology & Visual Science
2001;42:2686-2694
45. Saiko UCHIDA, Yasuyuki SUZUKI, Makoto ARAIE,
Takashi SHIGEEDA, Takeshi HARA, Shiroaki
SHIRATO. Long-term follow-up of initial 5-fluorouracil trabeculectomy in primary open-angle glaucoma in Japanese patients. Journal of Glaucoma
2001;10:458-465
46. Kiyoshi ISHII, Atsuo TOMIDOKORO, Miyuki
NAGAHARA, Yasuhiro TAMAKI, Mikiko KANNO,
Yasuhiro FUKAYA, Makoto ARAIE. The effects of
topical latanoprost on optic nerve circulation in rabbits, monkeys and humans. Investigative
Ophthalmology & Visual Science 2001;42:2957-2963
47. Takashi SHIGEEDA, Atsuo TOMIDOKORO, Makoto
ARAIE, Nobuyuki KOSEKI, Seiichiro YAMAMOTO.
Long-term follow-up of visual field progression after
trabeculectomy in progressive normal-tension glaucoma. Ophthalmology 2002;109:766-770
48. Miyuki NAGAHARA, Atsuo TOMIDOKORO,
Sawako SANDO, Makoto ARAIE, Sumiyoshi
TANAKA. MD., Ph.D. MD., Ph.D. An apparatus forcolor Doppler imaging in seated subjects. American
Journal of Ophthalmology 2002;133:270-272
49. Hiroshi MATSUO, Atsuo TOMIDOKORO, Yasuyuki
SUZUKI, Shiroaki SHIRATO, Makoto ARAIE. Lateonset transconjunctival oozing and point leak of
aqueous humor from filtering bleb after trabeculectomy. American Journal of Ophthalmology 2002; 133:
456-462
50. Chihiro MAYAMA, Yasuyuki SUZUKI, Makoto
ARAIE, Kyoko ISHIDA, Akira TSUJI, Tetsuya
YAMAMOTO, Yoshiaki KITAZAWA, Shigeo
FUNAKI, Motohiro SHIRAKASHI, Haruki ABE,
Hidetoshi TSUKAMOTO, Koji OKADA, Hiromu K
MISHIMA. Myopia and advanced-stage open angle
glaucoma. Ophthalmology (in press)Department ofOtorhinolaryngology,
Head and Neck surgery
Outlines
The Department of Otorhinolaryngology was founded in 1899 by Prof. Waichiro Okada.
This is the first department of otorhinolaryngology of the medical school and the university
hospital in Japan. The first professor, Waichiro Okada (1902-1924), the 2nd, Taneji Masuda(1924-1946), the 3rd, Kotoji Satta, the 4th, Ichiro Kirikae (1947-1969), the 5th, Yasuo Sato
(1970-1980), the 6th, Yasuya Nomura (1980-1991), the 7th, Kimitaka Kaga (1992-)

Research Objectives
Our department covers all of otorhinolaryngological diseases and associated systemic
diseases, and has specialized clinical and basic research in middle ear and inner ear diseases,
peripheral and central deafness in infant and children, adult and elderly, facial paresis, vertigo and balance disorders, olfactory disorders, paranasal diseases, voice and speech disorders, cleft palate, taste and swallowing disorders, head & neck cancer, psychosomatic medicine and medical education.
1) Hearing research; Morphology and neurophysiology of the inner ear focusing on sensory
neural deafness: human temporal bone pathology, electron microscopic study in animalmodels with gene abnormality, clinical application of otoacoustic emissions and auditory
brainstem responses. Hair cell physiology of synaptic transmission.
2) Facial nerve research; Morphology of the facial nerves focusing on degeneration andregeneration.
3) Head and neck cancer research; Molecular biology and gene therapy of head and neckcancers.
4) Evoked potential research; Generators of auditory evoked potentials in the central auditory system.
5) Auditory perception and cognition research; normal subjects and patients with central
deafness and cochlear implant using event related potentials and MEG.
6) Voice research; Morphology and electrophysiology of the larynx and voice production.
7) Basic research on auditory brainstem implant.
8) Vestibular research; The oculomotor and balance system in the brainstem, cerebellum andcerebrum. Vestibular myogenic evoked potential and its origin and clinical application.
9) Taste research; Taste perception and disorders.
10) Olfactory research; Olfactory epithelium morphology and function of olfaction.
11) Language research; Development of hearing, speech and language in neonates andinfants.
12) Artificial organ research; Development of artificial sensory and motor organs.

Faculties and Students
Professor
Associate Professor
Lecturer

Kimitaka Kaga, MD,PhD (1992-)
Masashi Sugasawa, MD,
Tatsuya Yamasoba, MD
Toshihisa Murofushi, MD,PhD,
Naonobu Takeuchi, MD,PhD
Ken Ito, MD,PhD,
Kenichiro Ishio, MD
Ryuzaburo Higo, MD,PhD

Associate ...............................10
Postdoctoral Fellow ................2
Graduate Student....................6
Research Student ....................4
Secretary .................................3277

Past Research and Major Accomplishments

Current Research

Otology and neurotology
1. Development of new surgical procedure: total middle ear reconstruction and auricle, canal plasty andossicular reconstruction for congenital microtia
and atresia.
2. Comprehensive study on central auditory systemand central auditory disorders.
3. Demonstration of origins of auditory evoked
potentials in animal and human subjects: auditory
brainstem response and middle latency.
4. Introduction of gene therapy into inner ear diseases. 5. Demonstration of sound lateralization ofbone conduction hearing.
6. Invention of bilateral bone conduction hearing aid.
7. Discovery of a new hearing disorder of auditory
nerve disease.
8. Proposal of new critical age of language development.
9. Mechanism of perception and cognition of musicand environmental sounds.
10. Discovery of a new antibody of inner ear.

Otology and neurotology
I. Clinical research
1. Early operation of cochlear implant around two
years of age.
2. Music perception of children and adults withcochlear implant.
3. Sound lateralization perception and time-intensity
trading ability in normal subjects with absolute
pitch and patients with brain damage.
4. Development of super-low noise bone conduction
hearing aid.
5. Cooperative reconstruction surgery of auricle andcanal plasty for congenital microtia and atresia byplastic surgeons and otological surgeons.
6. New total middle ear reconstruction surgery for
infectious radicalized ears.
7. Implantation of bone anchored hearing aid forchildren with Treacher Collins syndrome.
8. Early discovery of congenital deafness in neonatesand early hearing aid fitting and education of
speech and language.
9. Contribution to double handicapped children withhearing problem.
10. Perception and cognition of cortical deafness.

Head and Neck Cancer:
1. Long term follow up study on different treatmentof maxillary cancer and proposal of the best treatment.
2. Identification of adeno virus in nasopharyngeal cancer.
3. Development of new chemotherapy of head andneck cancer.
4. Development of new surgical procedure for parapharyngeal tumor.
Rhinology:
Demonstration of developing and aging changesof olfactory neuroepithelium.
Laryngology:
Development of new artificial voice production
system for patients after total laryngectomy.
Bronchoesophagology
Development of electrophysiological swallowing
system.
Medical eduacation:
1. Introduction of clinical counselling with head andneck cancer patients for medical students in bedside learning.
2. Evaluation system of teachers in medical school
by medical students.

278

II. Basic study
1. Development of polyimide multiple-site surface
microelectrode for epidural cortical recording ofhigh spatial resolution evoked-potentials.
2. Development of independent component analysis
of multiple-site auditory evoked potentials.
3. Molecular biology of inner ear hair cell differention.
4. Molecular biology of experimental noise induced
deafness.
5. Regeneration mechanism of inner ear hair cells inchick.
6. Development of gene therapy for experimental
inner ear diseases.
7. Origin of binaural interaction of hearing using
midline section of brainstem and localized lesionsof brainstem in animal models.
8. Plasticity of central auditory system.

Head and neck surgery
1. Development of a new procedure of skull base surgery.
2. Molecular biological study on hypopharyngeal
cancer.
3. Development of a new procedure of partial laryngectomy.

4. Quality of life between conservative and surgicaltreatment.
5. Development of navigation to support safer headand neck surgery.
Rhinology
1. Olfaction change of human subjects under environment of modern society.
2. A study on distribution of histamine receptor inhuman nasal mucosa.
3. Application of navigation system for endoscopic
nasal surgery.
Laryngology, Bronchoesophagology
1. Application of Botulinus toxin to treat spastic dysphonia.
2. A new procedure to treat hoarseness in elderly
patients inplanting fascia in the vocal cord.
3. Language development of children using tracheal
canula in the first year of life.
4. Comparative study of vocal cords in differential
species.
5. Measurements of pressure changes of swallowing
system in patients with dysphagia.
6. Surgical procedures to treat dysphagia.
Medical education
1. How to teach humanity in medical education.
2. Development of assessment of teachers activity in
lectures, seminars and bedside learning in medical
education.

Future Prospects
New artifial sensory and motor organs and genetherapy will be new directions checked by gene analysis of each cancer individually and treated by
1. Otology: After present cochlear implant for profound sensory deafness, we will challenge to create a new cochlear implant for music perception,
auditory brainstem implant for neural deafness
and super low noise bilateral bone conduction
hearing aids for conductive deafness.
2. Head and neck surgery: Head and neck cancer
treatment will be checked by gene analysis of eachcancer individually and treated by gene therapy
due to phylosophy based on tailored medicine.
3. Rhinology: Allergic rhinitis is incurable diseases
but will be challenged by new immunotherapy.
Sensory and neural anosmia is desperate to recover at present but will be challenged to innovate
artificial sensory device for implantation in olfactory bulb.
4. Laryngology: Voice is very important in communication. Loss of vocal cord result from total laryngectomy because of surgical cancer treatment.

Now we are challenging to innovate new computerized devices for providing the same voice fromthe oral cavity before surgery which uses voicesynthesis technology and orally fitted voice generating system.

Research Grants
1998 Hatamura Y, Ishii T, Kaga K: Advanced medical
tools for clinicians and development of fine instruments. Ministry of Welfare. 1998-2001, Total¥400,000,000.
1999 Kaga K, et al: Basic study on auditory brainstem
implant. Ministry of Education. 1999-2001, Total¥14,000,000.
2000 Kaga K, et al: Study on auditory space in higher
brain. Ministry of Education. 2000-2001, Total¥6,000,000.
2001 Kaga K: Identification of sound localization inhuman brain. Ministry of Education ¥2,100,000.
2002 Kaga K, et al: Neonatal universal screening andlong term follow up. Ministry of Welfare and Labor¥1,260,000.

Select Publications
1. Kaga K, Uebo K, Sakata H, Abe Y, Haebara H,
Kosakai M: Auditory brainstem responses and temporal bone and brainstem pathology in brainstem
death, with special reference to autolysis of red
blood cells. Acta Otolaryngol (Stockh) 115:183186,1995.
2. Kaga K, Tanaka Y: Auditory air and bone conduction
brainstem responses and damped rotation test foryoung children with bilateral congenital atresia ofthe ears. Int J Pediat Otorhinolaryngol 32:1321,1995.
3. Kaga K, Tamai F, Kitazumi E, Kodama K: Auditory
brainstem responses in children with Cornelia deLange syndrome. Int J Pediat Otorhinolaryngol
31:137-146,1995.
4. Kaga K, Nakamura M, Shinogami M, Tsuzuku T,
Yamada K, Shindo M: Auditory nerve disease of bothears revealed by auditory brainstem reponses, electrocochleography and otoacoustic emissions.
Scandinavian Audiol 25:233-238,1996.
5. Ismail Noorhassim, Kaga K: Pure tones audiometry
and auditory brainstem responses in noise-induced
deafness. American J Otolaryngol 17:31-35,1996.
6. Suzuki M, Kaga K: Effect of cisplastin on the negative
charge barrier in strial vessels of the guinea pig. A
transmission electron microscopic study using polyethyleneimine molecules. Eur Arch Otorhinolaryngol
253:351-355,1996.
7. Yamada K, Kaga K, Uno A, Shindo M: Sound lateralization in patients with lesions including the auditory cortex: comparison of interaural time difference(ITD) discrimination and interaural intensity difference (IID) discrimination. Hearing Research 101:173180,1996.

279

8. Yamasoba T, Oka Y, Tsukuda K, Nakamura M, Kaga
K: Auditory findings in patients with maternallyinherited diabetes and deafness harboring a point
mutation in the mitochondrial transfer RNAleu(UUR)
gene. Laryngoscope 106:49-53,1996.
9. Yamasoba T, Suzuki M, Kaga K: Influence of chronic
kanamycin administration on basement membraneanionic sites in the labyrinth. Hearing Research
102:116-124,1996.
10. Kaga K, Shindo M, Tanaka Y: Central auditory information processing in patients with bilateral auditory
cortex lesions. Acta Otolaryngol (Stockh) Suppl
532:77,82,1997.
11. Tanioka H, Kaga K, Zusho H, Araki T, Sasaki Y: MRof the endolymphatic duct and sac: findings in
Meniere disease. AJNR Am J Neuroradiol 18:4551,1997.
12. Suzuki M, Kaga K: Effect of cisplatin on the basement membrane anionic sites in the ampulla, macula, and strial vascularis of guinea pigs. Ann Otol
Rhinol Laryngol 106:971-975,1997.
13. Nakamura M, Yamasoba T, Kaga K: Changes in otoacoustic emissions in patients with idiopathic sudden
deafness. Audiology 36:121-135,1997.
14. Yamada K, Kaga K, Sakata H, Uno A, Tsuzuku T:
Auditory evoked potentials under total spinal anesthesia in rats. Ann Otorhinolaryngol 10871092,1997.
15. Suzuki Y, Kaga K, Sugiuchi Y, Ishii T, Suzuki J-I,
Takiguchi T: Sudden bilateral hearing loss due togastric carcinoma and its histological evidence. J
Laryngol Otol 111:1142-1146,1997.
16. Kojima Y, Kaga K, Shindo M, Hirose A:
Electromyographic examination of patients with unilateral cortical facial paralysis. Otolaryng Head Neck
Surg 117:S121-124,1997.
17. Kaga K, Uebo K, Sakata H, Suzuki J: Auditory andvestibular pathology in brainstem death revealed byauditory brainstem response. Acta Otolaryng(Stockh) Suppl 503:95-103,1993
18. Uno A, Kaga K, Tsuzuku T, Kuroki M: Middle-latency responses of awake and anesthetized Japanesemacaques. Audiology 32:302-307,1993.
19. Kim LS, Kaga K, Tsuzuku T, Uno A: Effects of primary auditory cortex lesions on middle latency
responses in awake cats. A.N.L. (Tokyo) 20:155165,1993.
20. Yamada K, Kaga K, Tsuzuku T, Uno A: Analysis ofauditory brain stem response with lidocaine injection into the cerebrospinal fluid in rats. Ann Otol
Rhinol Laryng 103:796-800,1994.
21. Yamada K, Kaga K, Suzuki J-I: Temporal bone pathology in patients without caloric response. Acta
Otolaryngol (Stockh) 114:586-594,1994.
22. Iwasaki S, Kaga K: Chronological changes of auditory
brainstem responses in Cockayne's syndrome. Int J
Ped Otolaryng 30:211-221,1994.
23. Kaga K, Uebo K, Sakata H, Abe Y, Haebara H,
Kosakai M: Auditory brainstem responses and temporal bone and brainstem pathology in brainstem

280

death, with special reference to autolysis of red
blood cells. Acta Otolaryngol (Stockh) 115:183186,1995.
24. Kaga K, Ichimura K, Kitazumi E, Kodama K, Tamai F:
Auditory brainstem respnses in infants an children
with anoxic brain damage due to near-suffocation ornear-drowning. Int J Pediatr Otorhinolaryngol
36:231-239,1996.
25. Kaga K, Nakamura M, Shinogami M, Tsuzuku T,
Yamada K, Shindo M: Auditory nerve disease of bothears revealed by auditory brainstem responses, electrocochleography and otoacoustic emissions.
Scandinavian Audiol 25:233-238,1996.
26. Iwasaki S, Kaga K, Yagi M, Kuroda M: Vestibular
findings syndrome. ORL 58:343-346,1996.
27. Kaga K, Shinoda Y, Suzuki J-I: Origin of auditory
brainstem responses in cats: Whole brainstem mapping, and a lesion and HRP study of the inferior colliculus. Acta Otolaryngol (Stockh) 117:197-201,1997.
28. Kaga K, Ichimura K: A preliminary report clinicaleffects of otic solution of ofloxacin in infantile
myringitis and chronic otitis media. Int J Pediaric
Otorhinolaryngol 42:199-205,1998.
29. Suzuki M, Yamasoba T, Kaga K: Development of theblood-labyrinth barrier in the rat. Hearing Research
116:107-112, 19989.
30. Suzuki M, Yamasoba T, Kaga K: Effects of chronic
administration of Kanamycin on the basement membrane anionic sites in the crista ampullaris of guinea
pigs. Laryngoscope 108:81-86,1998j.
31. Sakamoto M, Sugasawa M, Kaga K, Kamio T:
Average thresholds in the 8 to 20 kHz range as afunction of age. Scand Audiol 27:189-192,1998.
32. Kaga K, Ono M, Yakumaru K, Owada M, Mizutani T:
Brainstem pathology of infantile Gaucher's disease
with only wave I and II of auditory brainstem
response. J Laryngol Otol 112:1069-1073,1998.
33. Kaga K, Takeuchi N, Sakurai H: Facial nerve pathology of two patients with herpes simplex encephalitis.
A temporal bone study. Facial Nerve, pp 1-6, Proc
VIII International Symposium on the Facial Nerve.
Kugler Pub, The Netherlands, 1998.
34. Kaga K, Yamada K, Tsuzuku T, Uno A: The longterm effect of bilateral inferior colliculus ablation on
auditory brainstem response in awake cats. Acta
Otolaryngol (Stockh) 119:128-131m1999.
35. Kaga K: Vestibular compensation in infants and children with congenital and acquired vestibular loss inboth ears. Int J Pediatr Otorhinolaryngol 49:215224,1999.
36. Naito R, Murofushi T, Mizutani M, Kaga K: Auditory
brainstem responses, electrocochleograms, andcochlear microphonics in the myelin deficientmutant hamster 'bt'. Hearing Research 136:4448,1999.
37. Yamasoba T, Tsukuda K, Oka Y, Kobayashi T, Kaga
K: Cochlear histopathology associated with mitochondrial transfer RNALeu(UUR) gene mutation.
Neurology 52:1705-1707,1999.

38. Kaga K, Shindo M, Tanaka Y, Haebara H:
Neuropathology of auditory agnosia following bilateral temporal lobe lesions: A case study. Acta
Otolaryngol 120:259-262,2000.
39. Takegoshi H, Kaga K, Kikuchi S, Ito K:
Mandibulofacial dysostosis: CT evaluation of thetemporal bones for surgical risk assessment inpatients of bilateral aural atresia. Int J PediatricOtorhinolaryngol 54:33-40,2000.
40. Yamada K, Kaga K, Tsuzuku T, Uno A: Long-termchanges in middle latency response and evidence ofretrograde degeneration in the medial geniculate
body after auditory cortical ablation in cats. Acta
Otolaryngol 120:744-949,2000.
41. Itoh K, Yumoto M, Uno A, Kurauchi T, Kaga K:
Temporal stream of cortical representation for auditory spatial localization in human hemispheres.
Neruoscience Letters 292:215-219,2000.
42. Kaga K, Setou M, Nakamura M: Bone-conductedsound lateralization of interaural time difference andinteraural intensity difference in children and ayoung adult with lateral microtia and atresia of theears. Acta Otolaryngol 121:274-277,2001.
43. Setou M, Kurauchi T, Tsuzuki T, Kaga K: Binauralinteraction of bone-conducted auditory brainstem
responses. Acta Otolaryngol 121:486-489,2001.
44. Sheykholeslami K, Kaga K, Tsuzuku T, Mizutani M:
Electrophysiological measures of auditory function in
the neurofilament-deficient mutant quail (Quv).
Hearing Research 153:115-122,2001.
45. Kaga K, Sakurai H, Ogawa Y, Mizutani T, Toriyama
M: Morphological changes of vestibular ganglion
cells in human fetuses and in pediatric patients. Int J
Pediatric Otorhinolaryngol 60:11-20,2001.
46. Komura Y, Tamura R, Uwano T, Nishijo N, Kaga K,
Ono T: Retrospective and prospective coding for predicted reward in the sensory thalamus. Nature
142:546-549,2001.
47. Sheykholeslami K, Kermany MH, Kaga K: Frequency
sensitivity range of the saccule to bone-conducted
stimuli measured by vestibular evoked myogenic
potentials. Hearing Research 160:58-62,2001.
48. Kaga K, Yasui T, Yuge T: Auditory behaviors andauditory brainstem responses of infants with hypogenesis of cerebral hemispheres. Acta Otolaryngol
122:16-20,2002.
49. Kondo K, Sagara H, Hirosawa K, Kaga K, Matsushima
S, Mabuchi K, Uchimura H, Watanabe T: Hair cell
development in vivo and in vitro: analysis by using a
monoclonal antibody specific to hair cell in the chickinner ear. J Comp Neurol 445:176-198,2002.
50. Ishimoto S, Ho K, Sasaki T, Shinogami M, Kaga K:
Total middle ear reconstructive surgery for the radicalized ear. Otol Neurotol 23:262-266,2002.

281

Department of
Rehabilitation Medicine
Outline and Research Objectives
The Department of Rehabilitation Medicine was established by Ministry of Education,
Culture, Sports, Science and Technology in April 2001. It is one of the newest fields in the
University of Tokyo Graduate School of Medicine. It belongs to the Sensory and Motor
System Medicine Course of the Surgical Sciences Study Major. Current staff is only one professor. We have accepted the graduate school student formally since fiscal year 2001 when
the Rehabilitation Medicine Field was installed in. Two students of the first year class ofgraduate school and two of the second year class started some rehabilitation research. An
activity of our department is at one with the Central Rehabilitation Service of the university
hospital. As for the staff of the rehabilitation service of the university hospital, there are one
lecturer, one associate and three part-time medical doctors. In addition, one temporary associate has accompanied in April 2002, and he takes charge of the day hospital in psychiatry
rehabilitation.
The Central Rehabilitation Service derives from the establishment of the exercise therapy room in 1963 in the central medical service department. It aimed at the development of
the medical rehabilitation in our country corresponding to needs of rehabilitation service
that had become clear in the health care of the 20th century middle.
In the university hospital, the rehabilitation section increased and maintained ahydrotherapy room and the occupational therapy room, etc., and it was renamed the rehabilitation center in 1966. Then, it became an independent section by changing the title as
the central rehabilitation service in 1970. Both were names by measures in the hospital. A
formal name of the section was a department of physical therapy. The professor employment was set up as a full-time medical director in 1984. However, a formal name of the section was still a physical therapy department.
Rehabilitation medicine is a comprehensive medical management of disability including
its diagnosis and treatment. It was born in the flow of the health care and medical service atmodern ages by which it came to value the enhancement of not only extending years ofpatient’s life but also adding life to years. In Declaration of Alma-Ata by World HealthOrganization (WHO) of 1978, it was described, “primary health care addresses the main
health problems in the community, providing promotive, preventive, and curative and rehabilitative services”. Regardless of rapid expansion of those needs, acknowledgment of medical rehabilitation was delayed in the frame of conventional diagnosis and treatment department. In our country, it was 1996 that the rehabilitation department was authorized as theformal clinical department in the health insurance system by the former Ministry of Healthand Welfare. On the other hand, the professor of the physical therapy department was positioned as an assistance instructor in the sensory and motor system medicine course by the
University of Tokyo Faculty of Medicine having shifted to the graduate school course system between fiscal year 1995 and fiscal year 1997.
In the university hospital, the name was changed from the physical therapy department
to the rehabilitation medicine department by the budget measures in fiscal year 2001. Now
we integrated related occupational categories, which had historically belonged to the orthopedic surgery department and the former physical medicine department, and started themaintenance of the department. The Central Rehabilitation Service includes 14 physicaltherapists (one person is a part-time) and 5 occupational therapists and 5 acupuncture therapists as a rehabilitation team staff other than current medical doctors.
Our mission is to provide exceptional rehabilitation for our patients through clinicalexcellence and compassionate care, all dedicated to helping patients achieve their maximum
functional capacity and highest quality of life. Another significant focal point of the
Department is research. The research objectives of the Department are to make clear configuration of disabilities and to develop measures to reduce the obstacles for patients’ independent living as well as to promote reintegration in their society.

282

Faculties and Students
Professor and Chair Eto, Fumio, MD, Ph. D (1998~)
Lecturer
Kodama, Yoshiaki, MD, Ph. D
Associate .................................2
Visiting Fellow........................1
Graduate student ....................4
Secretary .................................1 (part-time employment)

Past Research and Major Accomplishments
The rehabilitation medicine field had not been
admitted as an established course before reorganization of the graduate school course system. Therefore,
there is still no own laboratory space. There is yet nospace of doctor’s medical office and other staff’s duty
rooms in the university hospital though the physicaltherapy department has been engaged in the medical
service activity of rehabilitation since 1963. In ourconventional research activity, a clinical research thatadheres to a daily medical management in rehabilitation has been a major subject.
Research topics that have been executed so far are
the following content.
1. The influence of the trouble in patient’s daily life
due to various diseases is analyzed, and an appropriate treatment program is developed. It is
included to describe natural course of the disease
and the trouble clearly in life cycle of physicallyhandicapped person. A study to make clear a pattern of the disorder type change in cerebral palsy
by the development process from infancy was
done. Natural course of Werdnig-Hoffmann disease and congenital muscular dystrophy, whichwere a rare pediatric disease, was described, andthe indication of rehabilitation was clarified.
2. Proper management of the factor disturbing rehabilitation process is important in everyday medical
rehabilitation care. The pain management was a
typical problem, and the pathophysiological study
on shoulder-hand syndrome in poststroke patientswas done.
3. Most of activities in daily life depend on walking
and locomotion ability. Especially, a study about
evaluation method of gait abnormalities anddevelopment of specific treatment of an abnormal
gait is necessary for regain of useful mobility inphysically disabled. The effect of various shoe
insoles including arch support as apparatus fortreatments was clarified by the gait analysis system.
4. We have studied on development of rehabilitation
therapy to promote independent living of thepatients with higher brain dysfunction due tocerebrovascular disorders, traumatic brain injury,
Alzheimer’s disease and so on. Such a study

included the development of assessment tools toevaluate the effectiveness of the rehabilitativeintervention.
5. The ordering a bed rest is one of the treatment
measures. We have clarified the meaning of disuse
syndromes in the rehabilitation as the adverse
effect, which includes the deconditioning state.
Moreover, decreased activity in daily life after discharge from hospital may be a significant cause of
disuse syndromes, especially in the older people.
The research on risk factors of accidental fall has
revealed that incidence of fall is higher in theolder people with decreased daily activities.
6. The disuse syndromes and hypoactive daily life
may be serious matter in the poststroke patientsliving in the community. We have examined theinfluence of daily activity on changes in the physical fitness of people with poststroke hemiplegia.
Then, we have concluded that they can improvetheir physical fitness without formal supervised
training by simply increasing their daily activities.
7. We have developed the comprehensive assessment
tool of activities of daily living (ADL) for the elderly based on the hierarchical structure of the ADL.
In rehabilitation of the dementia patients the usefulness of ADL measurement has been revealed
for classification of the severity of dementia as
well as for evaluation of the effect of rehabilitation
program.
8. A basic research including animal experiment isalso necessary to improve the rehabilitation management. In collaboration with some outside laboratories we have studied a causative mechanism ofmuscle atrophy, joint contracture and bone atrophy, which are main components of disuse syndromes. In addition, we have examined the effectof physical agents in such a condition; for example, effects of dietary calcium depletion and repletion on tibial bone volume, influences of exercise
and mechanical loading on bone strength, effects
of electrical stimulation for reducing the degree of
joint contracture, and so on.

Current Research
The department’s research interests are directed
towards reduction of the major disabilities of thehandicapped persons, namely immobility, instability
and intellectual impairment. The approach is boththeoretical, by seeking a better understanding of thebaneful processes which produce disability in daily
life of the handicapped persons; and practical by the
introduction and evaluation of new methods of management. Research workers of variety of medical andnon-medical backgrounds shall work together onthese problems. Such a research policy is the future283

directionality, but the present state is in extension of
the past research activities.
Two or more equipment (force platform, video
operation analysis system, surface electromyography,
and ataxiameter, etc.) are usually combined for theevaluation of walking and motion disturbances. This
combined operation analysis system is arranged forthe synchronized determination. In addition, synchronous measurements such as the torque machines forthe muscular power measurement and the surface
electromyography are possible. We have been analyzing human locomotion activities, and also examining
the effects of shoes with various insert or heel wedges
for walking in normal subjects and physically
impaired persons. The present research addresses
examining the effects of heel elevation of shoes on
walking of the patient with Parkinson’s disease.
Moreover, a biomechanical change in the walking pattern after surgical operation on the ligaments of theknee has been analyzed with those devices.
The accomplishment of human activities such as
locomotion requires the functional integration of atleast three major organic systems; the bone, joint, andmuscular system that carries out various motions indaily activities; central and peripheral nervous systemthat controls musculoskeletal system organs; cardiopulmonary system that supplies oxygen and glucose to the former two system organs. Therefore, clinical research interests of rehabilitation medicine are in
the development of integrated physical exercise program, the improvement of cardiopulmonary management during rehabilitation therapy, and restorative
design for brain damage and nerve injuries. Now weare studying on the evaluation of higher brain dysfunction concerning everyday activities and also on
the physical fitness measurement by using theergometer for the development of an appropriate
rehabilitation program.
The clinical practice of rehabilitation is characterized in the team approach by multidisciplinary cooperation. Because two or more specialized professionals
work together in practice, the area of research neededis broad. There are a lot of necessary, but unsettledresearch topics for development and enhancement of
rehabilitation practice. However, the physicians andnon-medical staffs cannot afford to spend time in the
research work because the needs of rehabilitation
medical service nowadays increase rapidly in the university hospital. Our present research environment isunder a poor condition, and therefore, more cooperation with the outside laboratory or organization
including other faculty of the university may be recommended to accomplish the research plan in order
to investigate a problem thoroughly.

284

Future Prospects
Rehabilitation medicine is an important task of primary health care. Theories of disability in health practice and research are area of a new frontier. A researchon treatment and prevention of disability depends onthe concept and the hypothesis of disability. In addition to an experimental study, a narrative based study
in ethnography is important so that the subjective
problems like disability experiences may be discussed.
Then, not only a biological approach but also a sociological approach should promote it concurrently.
Our academic field has just started. We haverequested a laboratory to accomplish experimental
study, but it is not given yet. Since historical process
and the financial situation of a current university, it ispessimistic to set up the research environment on theuniversity campus. We should struggle with the matter connected directly with the activity of the university hospital, which is a training organization of a
medical doctor, though there are an enormous number of unsolved research topics. We have entrusted
the attending lecturer to the staff of outside institutions and the organization in order to support ourclinical and educational tasks. We are now arranging
the cooperation system with staffs of these external
institutions for research and development of the welfare equipments to facilitate the independence of thedisabled persons. This system may be of help to theresearch activity coherent to clinical practice in rehabilitation.
The physical therapist and the occupational therapist are new type of jobs in our country in the development process, and they are positioned as medical
service staffs in the hospital. It is necessary toincrease the chance that those co-medical professionals also participate in the research activity in order toactivate a clinical research.
The research of rehabilitation medicine is a new
field, internationally. There increases a number ofinquiries to hope for studying at our department fromseveral foreign researchers of other Asian nations.
Unfortunately, our present environment is insufficientto accept them. Nevertheless, one Chinese doctor and
one Mongolia doctor are working with us now. The
former has already completed the doctor degree thesis,
and the latter is about to start a study now. Professor
Eto was invited to Chinese Rehabilitation Medicine
Association Conference held in Beijing in China in
October 2001 and gave a lecture, entitled “the current
situation of rehabilitation medicine in Japan, from aviewpoint of medical education”. In addition, he lectured several topics on stroke rehabilitation at the university hospitals in Wuhan city and Shijiazhuang city
in China. International cooperation in the rehabilitation medicine research is the future matter.

Table 1. Representative subjects for research grants

Amount of
Fiscal year Resource
Subject (Author)
money (yen)The MEXT ScientificStudy on effect of electric stimulation
1998-1999 Research Fund, Basicin prevention of disuse changes of
1,500,000
Research (C)bone and soft tissues (Dr. Akai, M)
The MEXT ScientificStudy on effect of heel elevation for
2000-2002 Research Fund, Basic
Parkinsonian gait (Dr. Eto, F)
4,100,000
Research (C)The MEXT ScientificStudy on functional recovery and ADL
2000
Research Fund, Basicof stroke patient's with higher brain
1,900,000
Research (C)dysfunction (Dr. Ohtsuru, I)
The MEXT ScientificStudy on evaluation of joint lesion by
2000
Research Fund, Basicusing noninvasive measures such as
3,100,000
Research (C)vibration response (Dr. Akai M)
Ministry of Health, Labor
Study on functional recovery and ADL
and Welfare, Researchin higher brain dysfunction (Dr. Eto, F)
2001-2002 Consignment Expense for
1,600,000
Psychiatric and Neurological
Disease(Abbreviation, MEXT: Ministry of Education, Culture, Sports, Science and Technology)

Research Grants
The total of the competing research expense,
which the doctor researcher who belonged to theCentral Rehabilitation Service of the university hospital acquired, is 13,200,000 yen since 1998. Five representative research topics and the capital sources are as
follows in table 1.

Select Publications
1. Ueda S, Miura T, Eto F. Shoulder-Hand Syndrome as
an important complication of hemiplegia. J Jap Ass
Phys Med Balneol Climatol 38: 35-42, 1975.
2. Eto F, Yoshikawa M, Morimatsu M, Hirai S, Ueda S.
Shoulder-hand syndrome as a complication of hemiplegia. Jpn J Geriat 12: 245-251, 1975.
3. Eto F, Ueda S. Long-term change of motor patterns in
cerebral palsy. Jpn J Rehabil Med 14: 261-266, 1977.
4. Eto F, Yoshikawa M, Ueda S, Hirai S. Posthemiplegic
shoulder-hand syndrome, with special reference torelated cerebral localization. J Am Geriatr Soc 28: 1317, 1980.
5. Eto F. Complications due to prolonged or excessive
rest in rehabilitation medicine. J Clinical andExperimental Medicine (Igaku no ayumi) 116: 416422, 1981.
6. Eto F. Activities of daily living of the patients withdementia in the long-stay psychogeriatric wards. In:
Flax HJ, Matta AA, eds. New Frontiers that Influence
Disease and Rehabilitation, IRMA IV, Puerto Rico,
1983, pp.125-129.
7. Watamori T, Eto F. A longitudinal study of linguistic
and nonlinguistic functions in a patient with
Alzheimer's disease. Rinshou Seishin Igaku (Clin
Psychiatry) 12: 1155-1168, 1983.

8. Eto F, Harasawa M, Hirai S. Hand dexterity related toage: Pegboard test as an indicator of aging and brain
dysfunction. Jpn J Geriat 20: 405- 409, 1983.
9. Eto F, Yoshikawa M. A dose-response study ofDihydroergotoxine (DHET) Mesylate for cerebrovascular disturbances. In: Gaitz CM, Samorajaski Y, eds.
Aging 2000: Our Health Care Destiny, vol 1:
Biomedical Issues, Springer-Verlag, New York, 1985,
pp.421-431.
10. Ueda S, Hasegawa T, Ando K, Sakuma A, Kusunoki
T. Standardization of the finger function test andupper extremity ability test for hemiplegia. Jpn J
Rehabil Med 22: 143-160, 1985.
11. Okawa Y, Ueda S, Eto F, Kikuchi N. The analysis of
the course of motor impairment in Fukuyama typecongenital muscular dystrophy. Jpn J Rehabil Med
22: 197-202, 1985.
12. Okawa Y, Eto F, Ueda S. The analysis of the courseof disability in Werdnig-Hoffman disease (chronictype). Jpn J Rehabil Med 22: 115-120, 1986.
13. Eto F. Treatment of degenerative neurological diseases in the elderly: a rehabilitation approach. Jpn J
Geriat 23: 35-40, 1986.
14. Eto F. Rehabilitation of post-stroke patients with cardiac disease. J Clinical and Experimental Medicine(Igaku no ayumi) 139: 691-695, 1986.
15. Ueda S, Eto F, Okawa Y. Standardization of a functional test for hemiplegia for the evaluation of total
body motion. Scand J Rehabil Med 17 (Suppl): 163,1988.
16. Eguchi K, Eto F, Ohkawa Y, Ueda S. Factors affecting
return to work following stroke in youth and young
adults. Jpn J Stroke. 10: 124-126, 1988.
17. Eto F. Physical disability and dementia. Jpn J Rehabil
Med 25: 85-86, 1988.
18. Eto F. Rehabilitation of the elderly patients. In: Hsu
C-J, Orimo H, eds. Problems of the aged. Asia &285

Pacific Council for Science & Technology, Taipei,
1989, pp64-88.
19. Majima M, Ueda S. Major factor of the deteriorationof physical fitness in poststroke hemiplegics. Jpn J
Rehabil Med 27: 53-57, 1990.
20. Eto F. Activities of daily living and mental status inelderly patients with organic brain disorders. In:
O'Neill D ed. Carers, Professionals and Alzheimer's
Disease, John Libbey & Company, London, 1991,
pp323-327.
21. Eto F. Falls and immobilization: A vicious circle in
the elderly. In: Orimo H, Fukuchi Y, Kuramoto K,
Iriki M eds. New Horizons in Aging, Univ of Tokyo
Press, Tokyo, 1992, pp.280-281.
22. Eto F, Tanaka M, Mizoguchi T. Comprehensive activities of daily living (ADL) index for the elderly. In
Beregi E, Gergely IA, Rajczi K, eds.: Recent Advancesin Aging Science, vol.2, Monduzzi Editore, Bologna,
1993, pp.2183-2187.
23. Obana M, Eto F. Progressive pes equinovarus complicated with Parkinson's disease. J Clin Rehabil 2: 7880, 1993.
24. Kakurai S, Akai M. Clinical experiences with a convertible thermoplastic knee-ankle-foot orthosis forpost-stroke hemiplegic patients. Prosthetics andOrthotics International 20:191-194, 1996.
25. Eto F, Saotome I, Akiya N, Furuichi T. Early intervention of rehabilitation service for acute stroke
patients. Eur J Neurol 3(Suppl 2): 102, 1996.
26. Akai M, Shirasaki Y, Tateishi T. Electrical stimulation on joint contracture; an experiment in rat modelwith direct current. Arch Phys Med Rehabil 78:405409, 1997.
27. Eto F. Rehabilitation of memory. Jpn J Rehabil Med
34: 395-399, 1997.
28. Akai M, Usuba M, Maeshima T, Shirasaki Y, Yasuoka
S. Laser's effect on bone and cartilage change
induced by joint immobilization; An experimentwith animal model. Lasers in Surgery and Medicine
21:480-484, 1997.
29. Kodama Y, Nakayama K, Fuse H, Fukumoto S,
Kawahara H, Takahashi H, Kurokawa T, Sekiguchi C,
Nakamura T, Matsumoto T. Inhibition of bone
resorption by pamidronate cannot restore normal
gain in cortical bone mass and strength in tail-suspended rapidly growing rats. J Bone Miner Res 12:1058-1067, 1997.
30. Usuba M, Akai M, Shirasaki Y. Effect of Low-Level
Laser Therapy (LLLT) on viscoelasticity of the contracted knee joint; Comparison with whirlpool treatment in rats. Lasers in Surgery and Medicine 22:8185, 1998.
31. Yokota K, Itsukaichi K, Kakurai S, Asakura K.
Consideration of training for walker-assisted gait:
From the investigation of the load under walker's
tips. Bull Jpn Soc Prosthetics Orthotics 14: 76-81,
1998.
32. Itsukaichi K, Kaneko H, Kakurai S, Tazawa E.
Habilitation of the congenital limb deficient children.
Bull Jpn Soc Prosthetics Orthotics 14: 88-94, 1998.

286

33. Eto F, Saotome I, Furuichi T, Ogasawara M. Effectsof long-term use of benzodiazepines on gait andstanding balance in the elderly. Annals of New York
Academy of Sciences 860: 543-545, 1998.
34. Kodama Y, Takeuchi Y, Suzawa M, Fukumoto S,
Murayama H, Yamato H, Fujita T, Kurokawa T,
Matsumoto T. Reduced expression of interleukin-11
in bone marrow stromal cells of senescence-accelerated mice (SAMP6): relationship to osteopenia withenhanced adipogenesis. J Bone Miner Res 13: 13701377, 1998, 1998.
35. Miyake N, Yanagihara K, Sindo N. House work offemale stroke patients. Jpn J Rehabil Med 36: 644648, 1999.
36. Kodama Y, Dimai HP, Wergedal J, Sheng M, Malpe R,
Kutilek S, Beamer W, Donahue LR, Rosen C, Baylink
DJ, Farley J. Cortical tibial bone volume in two
strains of mice: effects of sciatic neurectomy andgenetic regulation of bone response to mechanicalloading. Bone 25: 183-190, 1999.
37. Linkhart TA, Linkhart SG, Kodama Y, Farley JR,
Dimai HP, Wright KR, Wergedal JE, Sheng M,
Beamer WG, Donahue LR, Rosen CJ, Baylink DJ.
Osteoclast formation in bone marrow cultures from
two inbred strains of mice with different bone densities. J Bone Miner Res 14: 39-46, 1999.
38. Eto F. Recent advances in geriatric rehabilitation. Jpn
J Geriat 36: 153-161, 1999.
39. Xu H, Akai M, Kakurai S, Yokota K, Kaneko H. Effectof shoe modifications on center of pressure and inshoe plantar pressures, Am J Phys Med Rehabil
78:516-524, 1999.
40. Fujitani J, Ishikawa T, Akai M, Kakurai S. Influenceof daily activity on changes in physical fitness forpeople with post-stroke hemiplegia, Am J Phys Med
Rehabil 78:540-544, 1999.
41. Akai M, Shirasaki Y, Tateishi T. The effect of electricity on joint contracture due to immobilization;
Direct current stimulation in rat experiment. In:
Electricity and Magnetism in Biology and Medicine.
Bersani F ed., Kluwer Academic/Plenum Publishers,
New York, 1999, p.883-886.
42. Honda F, Akai M, Itsukaichi K, Kakurai S, Tazawa E.
A report on progress of trainings and obtained activities about electronic prosthesis fitting for the congenital limbs deficient child. Sagyo Ryoho (J Jpn Ass
OT) 18: 478-487, 1999.
43. Nara A, Umishima M, Imase A, Mineshima T. Studyon the effects of pulp-to-pulp distance in measuring
the pinch strength - compare the young with theaged in a nursing home -. Sagyo Ryoho (J Jpn Ass
OT) 19: 338-345, 2000.
44. Hirose K, Eto F. Exercise training for internal disability in the elderly. J Clin Rehabil 9: 3 42-350, 2000.
45. Eto F, Sakata T. Influential factors on health-related
quality of life after cerebral vascular disease. Jpn J
Geriat 37: 554-560, 2000.
46. Kodama Y, Miyakoshi N, Linkhart TA, Wergedal J,
Srivastava A, Beamer W, Donahue LR, Rosen C,
Baylink DJ, Farley J. Effects of dietary calcium deple-

tion and repletion on dynamic determinants of tibial
bone volume in two inbred strains of mice. Bone. 27:
445-452, 2000.
47. Kodama Y, Umemura Y, Nagasawa S, Beamer WG,
Donahue LR, Rosen CR, Baylink DJ, Farley JR.
Exercise and mechanical loading increase periostealbone formation and whole bone strength in
C57BL/6J mice but not in C3H/Hej mice. Calcif TissueInt. 66: 298-306, 2000.
48. Eto F. Causes of falls in the elderly. Japan Medical
Association Journal 44: 299-305, 2001.
49. Ohtsuru I, Eto F, Wada N, Saotome I, Furuichi T.
New reliable and valid motor assessment scale forstroke patients: Hemiplegic motor behavior tests.
Geriatrics Gerontology Int 1: 45-51, 2001.
50. Kodama Y, Eto F. How to find out patients with ahigh risk for falls. J Clin Rehabil 10: 961-964, 2001.

287

Department ofAnesthesiology
Outline and Research Objectives
The department of Anesthesiology was established in1952. Our department has residents and eight researchers from China. We give lectures and provide clinical education for
postgraduate students and medical students.
We have pain clinic services in our department, which was established in 1962. It is provided for not only out-patients but also including patients in the ward of the other departments on a daily basis in all areas of painful diseases.
Anesthesia service including pre-and post-operative care is provided every day for elective and emergency surgical procedures. Recently, we have started acute pain service forpostoperative pain relief and palliative medicine for cancer pain relief and terminal care.

Research activities:
There are eight laboratories in our department, which are investigating clinical and basic
project of anesthesia research.
These themes of the research groups of our department are listed as bellow.

Perioperative
anesthesia
management for
surgical patient
respiration
Emergency medicine
circulation
General anesthesia

Intensive care medicine

New
deviceandtechniqueforanesthesia
andpain medicine

Muscle relaxation
Resusitology

Local anesthesia

Shock
Pain medicine

Perioperative
Pain physiology

Palliative medicine

QOL

behavior

Anesthesiology, basic and clinical respiration
・ Measurement of pulmonary vascular resistance of normal and pulmonary edema using
rabbit・ The effect of anesthetics upon pulmonary function
・ The model of neurogenic pulmonary edema of rabbit
・ Basic research of lipopolysaccharide which interact with apoprotein from the lung of
neonatal mouse
・ Basic research of the changes in transmission and distribution of gas with pulmonary
lesion・ Clinical assessment of pulse-oximeter288

circulation
・ Relationship between sympathetic nervous system and cardiac function
・ Clinical assessment of anti-hypertensive agents during anesthesia
・ Prostaglandins and tissue blood flow of the liver and kidney
pain mechanism (neurobiology, neuro-physiology, behavior investigation)
・ Relationship between noxious stimuli and catecholamines in the anesthetized rat
・ Physiology of pain and the mechanisms of analgesia using spinal rat
・ The effect of midazolam upon the spinal analgesical mechanisms
・ The effect of peripheral sensory nervous activities by acupuncture
・ Basic and clinical assessment of benzodiazepine antagonist
・ Basic and clinical assessment of enkepharinase inhibitor・ Analgesic mechanism of nociceptin in spinal rat
・ Assessment of bispectral index monitor
・ Clinical evaluation of drug challenge test
・ Analgesic mechanism of laser treatment
・ Analgesic mechanism of oriental medicine
・ Clinical assessment of acupuncturemuscle relaxation
・ Mechanism and the pharmacological analysis of non-depolarizing muscle relaxants inhuman
・ Clinical assessment of malignant hyperthermia
・ Basic and clinical assessment of non-depolarizing muscle relaxants
new devices and techniques for anesthesia
・ Mechanism of H-type epidural-spinal anesthesia
・ Development of skin surface anesthetics by lidocaine tape・ Clinical assessment of the induction by midazolam combined with barbiturates
・ Anesthetic method by low dose buprenorphine with inhalational anesthetics
・ The effect of epidural buprenorphine and morphine on post-operative pain control
・ Clinical usefulness of patient-controlled analgesia (PCA)・ Clinical assessment of stellate ganglion block・ Assessment of anesthetic machines
・ Development of device for intubation
mechanism of anesthesia
・ Mechanism of anesthetics from auditory brainstem response and Fourier analysis of
EEG・ Inhalational anesthetics and rate potential
・ Analgesic mechanisms of hyperventilation
・ The interaction of central analgesic and spinal analgesic mechanisms
shock・ Response to immunological system against the endotoxin in the blood
・ The effect of poly-enzyme inhibitor upon tissue microcirculation
・ Effects of anesthetics upon liver cell and Kupffer cell
QOL in surgical patients during perioperative period and chronic pain patients・ Perioperative QOL in case of surgical patient
・ QOL of donor of blood
・ QOL of intractable chronic pain patient such as post-herpetic neuralgia and low back
pain

289

Faculty and Students

Future Project

Professor and Chair Kazuo Hanaoka, MD, Ph., D. (1991~)
Associate Professors Hideko Arita, MD, Ph.,D.
Tomoki Nishiyama MD, Ph., D
Lecturer
Cyoku Yajima, MD, Ph., D
Yasuo Ide, MD, Ph.,D.
Masakazu Hayasida MD, Ph.,D.
Associate ...............................13
Postdoctoral Fellow ..............12
Graduate student ....................9
Research student.....................6
Secretary .................................3

We are seeking the method of safe anesthesia
including perioperative period. Also safe managementof pain is really necessary in 21 century, because thepopulation of aged people will be tremendously
increased. Therefore, the investigated area of above
mentioned will be continued. Palliative care medicine
will be important field also in the near future.
Therefore, we will investigate this field. Actually clinical investigation of palliative care medicine has started from this year as a field study.

Research Grants
Past Research and Major Accomplishments
In Anesthesiology, Respiration, Circulation, Pain,
Muscle relaxation, New devices and techniques foranesthesia, Mechanism of anesthesia, Shock andPerioperative QOL are mainly involved.
For each project, we are investigating both basically and clinically. The main purpose of these investigation is that the safety and quality of perioperative
anesthesia care are sought, and also the treatments ofpatients with intractable pain as chronic pain andpostoperative pain as acute pain are important field of
pain management.
We investigated the effect of Drug Challenge Test
(DCT) for chronic intractable pain patient and established the easy and accurate method of DCT. This
DCT were applied to many chronic patients and got
good results by the treatment of administered adequate drugs orally. Epidurascopy for chronic lumbar
pain are investigated and developed clinically.
Postoperative pain management are also investigated and established guideline for the method using
local anesthetics combined with narcotics via epidural
catheter to the epidural space. Patient Controlled
Analgesia (PCA) and pre-emptive analgesia are also
investigated.

Current Research
Respiration, circulation, pain, muscle relaxation,
new devices and techniques for anesthesia, mechanism of anesthesia, shock and perioperative QOL arebeing investigated. Each project is progressing well.
Especially new devices for epiduroscopy with usefulattachment such as manipulating device are being
developed.
We are making of the animal model of post herpetic neuralgia (PHN), which is very useful for the investigation of PHN. The number of patients with PHN
will increase because of large population of high aged
people in the near future. Therefore, this is very
important investigation.

290

1. 1998-2001 Research Grant (C2), #10671404 The
Involvement of NMDA receptor in the intrinsic
analgesia evoked by hyperventilation.
2. 1998-2001 Research project. Grant-in-aid for scientific research (B)#10470315 The effects of vasoactive drugs upon the spinal pain modulation.
3. 1999-2002 Research Grant (C2), #11671480
The effects of inhalational anesthetics and nitricoxide upon the activities of spinal dorsal hornneuron.
4. 2000-2002 Research Grant (C2), #12671453
Investigation of network by analgesic mechanismsof spinal cord
5. 2002-2004 Research Grant(C2), #14571422 The
development and clinical application of cheeper
and more accurate neuromuscular monitoring
devices now in use.

Select Publications
respiration
1. Kitamura T, Uchida K, Tanaka N, Tsuchiya T,
Watanabe J, Yamada Y, Hanaoaka K, Seymour JF,
Schoch OD, Doyle I, Inoue Y, Sakatani M, Kudoh S,
Azuma A, Nukiwa T, Tomita T, Katagiri M, Fujita A,
Kurashima A, Kanagasaki S, Nakata K:Serologicaldiagnosis of idiopathic pulmonary alveolar proteinosis. American Journal of Respiratory & Critical
Care Medicine 162:658-662, 2000
circulation
2. Nishiyama T, Hanaoaka K,: Nicardipine did not activate rennin-angiotensin- aldosterone system duringisoflurane or sevoflurane anesthesia. Canadian
Journal of Anaesthesia 47(12):1249-1252,2000
3. Nishiyama T, Hanaoaka K: Free hemoglobin concentrations in patients receiving massive blood transfusions during emergency surgery for trauma.
Canadian Journal of Anaesthesia 47(19): 881-885,
2000
4. Nishiyama T, Yokoyama T, Matsukawa T, Hanaoka
K: Continuous nicardipine infusion to control bloodpressure after evacuation of acute cerebral hemorrhage. Canadian Journal of Anaesthesia 47(12):11961201,2000
5. Orii R, Sugawara Y, Hayashida M, Yamada Y, Kubota
K, Takayama T, Harihara Y, Makuuchi M, Hanaoaka
K:Peri-operative blood lactate levels in recipients ofliving-related liver transplantation. Transplantation
69(10):2124-7, 2000
6. Takeda K, Sawamura S, Tamai H, Hagihara R,
Hanaoaka K: Reversible tricuspid valve obstruction
during removal of renal cell carcinoma with intracardiac tumor extension. Anesthesia & Analgesia
91:1137-38, 2000
7. R. Orii, Y. Sawamura, M. Hayashida, Y. Yamada, K
Chang, T. Takayama, M. Makuudhi and K.Hanaoka:
Effects of amrinone on ischaemia-reperfusion injury
in cirrhotic patient undergoing hepatectomy: a comparative study with prostaglandin E1. British Journalof Anaesthesia 85(3): 389-95, 2000
8. Orii R, Sugawara Y, Hayashida M, Uchida K, Yamada
Y,Takayama T., Makuuchi T., Hanaoka K: Lactate iscorrelated with the indocyanine green elimination
rate in liver resection for cirrhotic patients.
Anesthesia & Analgesia 92(4):1064-070,2001
9. Kazuo Hanaoka, Akiyoshi Namiki, Shiji Dohi,
Yoshihisa Koga, Osafumi Yuge, Yasushi Kayanuma,
Kazuyuki Hidaka, Tadashi Kusunoki; A dose-ranging
study of midazolam for postoperative sedation ofpatients: A randomized, double- blind, placebo-controlled trial. Crit Care Med. 30 (6): 1256-1260, 2002
10. Masakazu Hayashida, Mieko Chinzei,, Haruko
Fujiwara, Kyoko Komatsu, Hisako Usui, Kanji
Uchida, Toshiya Tomioka, Kazuo Hanaoka:
Bispectral Index as an Indicator of Cerebral Function
during Surgery Using Deep Hypotheremia andCirculatory Arrest. Cardiovascular Anaesthesia 6(1):9-13, 2002

pain mechanism (neurobiology, neuro-physiology,
behavior investigation)
11. Tomoki Nishiyama, Takeshi Yokoyama, Kazuo
Hanaoka: Midazolam improves postoperative epidural analgesia with continuous impression of local
anesthetics. Canadian Journal of Anaesthesia 45(6) :551-555, 1998
12. T. Nishiyama and K. Hanaoka: Effect of diluent volume on post-operative analgesia and sedation produced by epidurally administrated Midazolam.
European Journal of Anesthesiology 15: 275-279,
1998
13. T. Nishiyama, T. Matsukawa and K. Hanaoka:
Continuous epidural administration of Midazolam
and Bupivacaine for postoperative analgesia. Acta
Anaethesiolgica Scandinaviva 43 : 568-572, 1999
14. Tomoki Nishiyama, Takashi Matsukawa, Kazuo
Hanaoka: Acute Phase Histopathological Study ofSpinally Administered Midazolam in Cats.
Anesthesia & Analgesia. 89: 717-20, 1999
15. Hanaoaka k, Hayashida M,Arita H, Sumida T, Ide
Y:Management of Postoperative Pain. The

Management of Acute and Chronic Pain The Use of
the Tools of Trade: 133-137,2000
16. Hanaoka K, Meno A, Arita H, Tamai H, Orii R,
Sumida T: Drug Challenge Tests in Chronic PainManagement. The Management of Acute andChronic Pain TheUse of the Tools of Trade: 345349,2000
17. H. Sekiyama, J Utsumi, S G Shimada, H Nagase andMeno A, Arita H, Hanaoaka K:The Efficacy of Drug
Challenge Test (DCT) in the Treatment of Pain
Attributable to Brachial Plexus Avulsion,
Management of Pain. World Perspective:183-186,
2000
18. Nishiyama T, Hanaoaka K: The effects of epidural
bupivacaine, morphine, and their combination on
thermal nociception with different stimulus intensity
in rats. Anesthesia &Analgesia 91(13) :652-656, 2000
19. Arita H, Meno A, Zhang L, Hanaoka K: The CPT and
Drug Treatment for Brachial Plexus Avulsion,
Management of Pain. A World Prespective:115-8,
2000
20. Nishiyama T, Gyermek L, Lee C, Kawasaki –Yatsugi
S, Yamaguchi T, Hanaoaka K:The analgesic interaction between intrathecal clonidine and glutamate
receptor antagonists on thermal and formalininduced pain in rats. 92 Anesthesia & Analgesia (3):725-732,2001
21. Hanaoaka K: Drug Challenge Tests in Chronic Pain
Patients. The role of catecholamines and other neuromediates in neuropathic pain. Proceeding of theSatellite Symposium of the 9 th International
Catecholamines Symposium: 69- 81,2001
22. Toshiya Tomioka, Yutaka Awaya, Kenji Nihei andKazuo Hanaoka: Post- Herpetic neuralgia in a patientwith congenital insensitivity to pain and anhirosis
Journal of Anesthesia 16(1): 84-6,2002
23. S. Swamura, T. Tomioka, and K. Hanaoka: The
Importance of Tail temperature monitoring during
tail-flick test in Evaluating the antinociceptive actionof valatile anesthstics. Acta Anaesthesiologica
Scandinavica 46:451-4, 2002
24. Hanaoka K., Hayashida M., Arita H., Sumida T., Ide
Y.: How to Set up an Acut Pain Service. Japan
Perspective, Recent Views on Clinical Pain Edited
by Varrassi G. Monduzzi Editor, Bologna: 93-97,
2002
25. Min Dai, Toshinobu Sumida, Megumi Tagami, Yasuo
Ide, Masaki Nagasae, Hiroshi Sekiyama and Kazuo
Hanaoka: Suppressive effect of spinal dorsal-horn
neuronal activity by local spinal-cord cooling inreversed by naloxone in cats. Journal of Anesthesia
16: 211-15, 2002
26. Li WM., Wu GC., Arita H., Hanaoka K.: Acupuncture
stimulation inhibits somoato-renal sympathetic Aand C-reflexes in anesthetized rats. Acupuncture &Electro-Therapeutics Research 27(2): 119-27, 2002.

muscle relaxation
27. Hideto Oyamada, Keiko Oguchi, Naoto Saitoh,Toshiko Yamazawa, Kenzo Hirose, Yoko kawara,291

Kazunao Wakatsuki, Katsuji Oguchi, Megumi
Tagami, Kazuo Hanaoka, Makoto Endo,andMasamitu Iino: Novel Mutations in C-teminal channel Region of the Ryanodire Receptor in Malignant
Hypermia Patients. Jpn. J. Pharmacol.88:159-166,
2002

new devices and techniques for anesthesia
28. Tomoki Nishiyama, Takashi Matsukawa, Kazuo
Hanaoka: The Effect of Age and Gender on the
Optimal Premedication Dose of Intramuscular
Midazolam. Anesthesia & Analgesia 86: 1103-1108,
1998
29. T. Nishiyama, N. Sugai and K. Hanaoka: Inivitro
Changes in the Transparency and PH of Cerebro
Spinal Fluid Caused by Adding Midazolam. European
Journal of Anaesthesiology 15: 27-31, 1998
30. Tomoki Nishiyama, Hideto Nakayama, Kazuo
Hanaoka,: Sevoflurane or Thipotenal-Isoflurane forInduction and Laryngeal Mask Insertion?
Comparison by Side Effects; Hemodynamics, andSpectral analysis of Heart Rate Variability.
Anesthesia and Resuscitation 35(2) : 99-103, 1999
31. Takayuki Kitamura, Yoshitugu Yamada, Hong-Lin
Du, Kazuo Hanaoka: Efficiency of a New Fiberoptic
Stylet Scope in Tracheal Intubation. Anesthesiology
91(6) :1628-1632, 1999
32. Kitamura T, Yamada Y, Du HL, Hanaoka K: An efficient technique for tracheal intubation using theStylet Scope alone. Anesthesiology 92(4) :1210-1211,
2000
33. T. Kitamura, Y.Yamada, M. Chinzei, H.L.Du andK.Hanaoka: Attenuation of heamodynamic responses
to tracheal intubation by the Stylet Scope. British
Journal of Anaesthesia 86(2):275-277,2001
34. Kato,M. Sugiyama,Y. Orii,R. Hayashida,M. Kaneko,J.
Takayama,T. Hanaoka, K. Makuuchi,M : Lactate levels in cirrhotic patients undergoing liver resection.
Hepato-Gestroentreology 48 (40):1106-9,2001
35. Toshiya Tomioka, Yutaka Awaya, Kenji Nihei,
Hiroshi Sekiyama, Shigehito Sawamura, Kazuo
Hanaoka : Anesthesia for Patients with Congenital
Insentivity to Pain and Anhidrosis; A Questionnarire
Study in Japan. Anesthesia & Analgesia 94:271274,2002
36. Nobuhide Kin, Masakazu Hayasida, Kyung-ho
Chang, Kanji Uchida, Kazuo Hanaoka: External manual compression of the abdominal aorta to control
hemorrhage from a ruptured aneurysm. Journal of
Anesthesia 16: 164-6, 2002
37. Tomoki Nishiyama,, Takashi Mastukawa, Kazuo
Hanaoka: Effects of adding Midazolam on the
Postoperative Epidural Analgesia with Two Different
Doses of Bupivacaine. Journal of Clinical Anesthesia
14: 92-7, 2002
38. Nishiyama T., Misawa K., Yokoyama T., Hanaoka K.:
Effects of combining Midazolam and Barbiturate on
the response toracheal intubation : changes in autonomic nervous system. Journal of Clinical Anesthesia
14(5):344, 2002

292

39. Nishiyama T., Hanaoka K., Ochiai Y.: The medianapproach to transsacral epidural block. Anesthesia &Analgesia 95(4): 1067-70, 2002
40. Tomoki Nishiyama, Takashi Mastukawa, Takeshi
Yokoyama, Kazuo Hanaoka: Rapid Inhalation
Induction with 7% Sevoflurane Combined with
Intravenous Midazolam.Journal of Clinical
Anesthesia 14:290-295, 2002

mechanism of anesthesia
41. Sawamura S, Kingery WA, Davies MF, Agashe G,
Clark DJ, Kobilka BK, Hashimoto T, Maze M:
Antinociceptive action of nitrous oxide is mediatedby stimulation of noradrenergic neurons in the brainstem and activation of alpha 2B adrenoceptors.
Journal of Neuroscience 20:9242-9251,2000
shock
42. T. Nishiyama, T. Yokoyama and K. Hanaoka: Effects
of sevoflurane and isoflurane anesthesia on arterial
ketone body ratio and liver function. Acta
Anaesthesiolgica Scandinavica 43: 347-351, 1999
43. Nishiyama T, Hanaoaka K: A traumatic asphyxia in achild. Canadian Journal of Anaesthesia 47:10991102, 2000
44. Nishiyama T, Matsukawa T, Hanaoka K: Is proteaseinhibitor a choice for the treatment of pre-or mild
disseminated intravascular coagulation? Critical Care
Medicine 28:1419-22, 2000
45. Takayuki Kitamura, Yoshitsugu Yamada, Yoshifumi
Beck, Sae Asai, Hong-Lin Du and Kazuo Hanaoka:
Postoperative left recurrent laryngeal nerve palsy
possibly caused by coincidental swelling of themetastatic mediastinal lymphonode. Journal of
Anesthesia 14(4):216-7,2000
46. Nishiyama T, Hanaoka K: Hemolysis in stored red
blood cell concentrates: modulation by haptoglobin
or ulinastatin, a protease inhibitor. Crit Care Med. 29(10):1978-82,2001
47. Nishiyama T, Hanaoka K: Do the effects of a protease inhibitor, ulinastatin, on elastase release byblood transfusion depend on interleukin 6 ? Crit CareMed. 29(11): 2106-2110,2001
48. Nishiyama T, Hanaoka K: Propofol-induced bronchoconstriction: two case reports. Anesthesia &Analgesia 93 (3): 645-646,2001
QOL pre-operation
49. Mina Nishimori, Akiko Takeoka, Arinobu
Tojyo,Yasuo Nakano, Yoshitsugu Yamada and Kazuo
Hanaoka: Self-reported recovery time of daily activity
after bone marrow harvesting from healthy doners.
Journal of Anesthesia 15:1-5,2001
50. Mina Nishimori, Nelly Moerman, Shunichi
Fukuhara, F. S. A. M. Van Dam, M.J. Muller, Kazuo
Hanaoka & Yoshitsugu Yamada: Translation and validation of the Amsterdam preoperative anxiety andinformation scale (APAIS) for use in Japan. Quality ofLife Research 11: 361-4, 2002

Department of Emergency
and Critical Care Medicine
OutlineDepartment of Emergency and Critical Care Medicine was established in 1965, as the
emergency service within the Central Clinical Service Facilities of the University of Tokyo
Hospital and at the same time as the intensive care service for in-hospital patients, it
became a tertiary emergency care and critical care center in the metropolitan Tokyo and also
became the principal teaching facility of the University of Tokyo. It is a designated Level I
Trauma Center, and also the home of one of the newest Life Flight aeromedical services in
the country.
The Emergency Center sees approximately 15000 patients per year. It contains major
trauma and cardiac resuscitation rooms complete with STAT X-ray and full monitoring andresuscitation equipment. There are 9 treatment spaces including space for orthopedic, gynecology, and optho-ENT evaluation. X-ray, rapid spiral CT, ultrasound, angiography and
STAT Lab are located adjacent to the Emergency Center.
The Critical Care Center contains adult intensive care unit (ICU) of 8 beds, cardiac careunit (CCU) of 6 beds, surgical high care unit (SHCU) of 36 beds, medical high care unit
(MHCU) of 15 beds, pediatric intensive care unit (PICU) of 6 beds, and neonatal intensive
care unit (NICU) of 6 beds.
The Emergency Center and Critical Care Center sees an excellent mix of multiple traumas, high-acuity medical, surgical, pediatric, and gynecological patients. The Life Flight
service provides another opportunity for exposure to critically ill patients. Consult services
are available from each of the clinical departments of the Hospital.

Faculties and Students
Professor and Chairman Naoki YAHAGI, M.D., Ph.D.
Associates ...............................9
Staff.........................................3
Research student.....................1
Secretaries ...............................3

Past Research and Major Accomplishments• Study of the effect of anesthetics on the thresholdfor transpulmonary passage of venous air emboli.
(Resuscitation 13: 81-86, 1986, Anesthesiology 67:
905-909, 1987, Anesth Analg 75: 720-723, 1992) .
We found that the threshold for transpulmonary passage of venous air was significantly
lower during halothane anesthesia (0.01-0.05
ml/kg), as compared with pentobarbital (1.0ml/kg), fentanyl (0.5 ml/kg), or ketamine (0.35
ml/kg) anesthesia.
• Study on the effect of catecholamine on regional
cerebral blood flow in dogs (Masui 36: 1176-1180,
1986)
Development of Hemoperfusion System (HF)
1) For the patients of cardiac surgery
2) For the regulation of water balance in the patientsof renal insufficiency
3) For the expansion of the indication of bloodlesspriming for cardiopulmonary bypass by hemoconcentration using HF.

The usage of HF during cardiopulmonary bypass in NCVC

1985

1986

1987

1988

1989

1990

Total

644

623

593

573

586

594

HF

13

78

115

84

120

180

HF in adults
(%)

13
2.0

56
9.0

83
12.0

44
7.8

67
11.6

97
16.3

HF in infants
(%)

0
0.0

22
3.5

32
5.4

40
7.0

52
8.9

83
14.0

293

• Development of HF pump system for the perioperative management of cardiac surgical patients suffering from renal insufficiency and deteriorated
cardiac function. (Ube-Junken; 1984)• Induction of hypothermia for the management of
the patient who undertaken open heart surgery
complicated by acute cerebral infarction (Kyukyuigaku 18:917-921, 1994) (1984).
• We elucidated the structural parts involved in activation and inactivation of Na channel by bioengineering and electrophysiology. (FEBS Letters 228:
195-200, 1987, Nature 339: 597-603, 1989) .
• Effect of low molecular weight dextran for ARDS
induced by oleic acid (Am J Emerg Med18: 180183, 2000)(1988).
• Yahagi cared 5300 cases of critically ill patients
including cardiac surgical patients, severely illpatients of all categories in NCVC, and emergency
cases. Yahagi developed a handy bronchofiberscope. (Easyscope:FiberTech, 21000BZZ00571000,1998). Yahagi engaged in the preparation of a manual for cardiac transplantation, and established
The International Society of Medical Gas in 1995.
• Induction of mild hypothermia for the management of severe cardiac insufficiency (Anesth Analg
79: 581-582, 1994 , J Clin Anesth 10: 120-125,
1998) (1991)

Inhaled nitric oxide (NO)1) Indication and the 2-4years follow up of the cases(Artif Organs 21: 17-20, 1997, Artif Organs 21: 8384, 1997, Artif Organs 22: 886-891, 1998, Artif
Organs 23: 169-174, 1999)

2) Fontan type operation (Ann Thorac Surg 57: 13711372, 1994)
3) LVAS (Artif Organs 19: 557-558, 1995, Ann Thorac
Surg 65: 345, 1998)• Helium inhalation (Anesth Analg 80: 1042-1045,
1995, Artif Organs 21: 24-27, 1997) We demonstrated the beneficial effect of helium/oxygen to
improve oxygenation of the postcardiac surgicalpatients who showed impairment of oxygenation
without physiological findings and with normal
chest radiographs despite having a positive end
expiratory pressure of up to 10 cmH2O.

The effect of helium-oxygen on oxygenation and lung parameters
Evaluation of Airway
1) Effect of change of position (Ann Thorac Surg min-90 minbaseline
He 90 min67: 894, 1999)
56*
PaO2/FiO2
117±45113±39174±56*
2) Ultrasound detection of diaphragmatic paraly- ±5* Qs/Qt (%)
27±7
29±6
19±5*
sis after cardiac operations (Ann Thorac Surg 18*
Cdyn (ml/cm H2O) 60±18
60±18
65±18*
65: 1841, 1998)±4
PIP (cm H2O)
25±4
25±3
25±4
3) Double lumen endobronchial tube Broncho- *: p<0.05 vs baseline values.
Cath II (Anesthesiology 81: 781-782, 1994)
4) The cause for needing airway maneuvers to • Autotriggering caused by cardiogenic oscillation
maintain a patent airway during the use ofduring flow-triggered mechanical ventilation (Crit
Care Med 28: 402-407, 2000)
cuffed oropharyngeal airway (COPA) using
endoscope, and the difficulty of maintaining • Clinical use of electrolyzed water (Artif Organs 21:
39-42,1997, Artif Organs 24:984-987, 2000).
patent airway during COPA use might by collapse of the larynx at the level of the hyoid • Elucidation of peripheral neural regulation of heart(Brain Res 761: 329-332, 1997, J Autonom Nerv
bone. (Resuscitation in press)
5) Diagnosis of airway obstruction (Anesth Analg
System 68: 43-48, 1998, Brain Res 794: 146-150,
76: 207, 1993, Anaesthesia 50: 91-92, 1995,
199, Brain Research 864: 157-161, 2000)
Anesth Analg 85: 1180-1181, 1997)
6) Bronchial lavage ofthe infant using alaryngeal mask airway ( Anaesthesia
49: 450, 1994)( Anaesthesia 49:
450, 1994)
7) Development of ahandy-type bronchofiberscope294

Current Research and Future Prospects
We are now concentrating to develop “the Vital
Care Network System” which is to manage the great
number of high risk people continually. The system iscomposed of wearable monitor, wrist watch type PHS
which is to amplify the signal, the information center
to receive and manage the vital sign signals and to callon hospitals for aid. (The Next Generation Software
Project of Information-technology Promotion Agency,
Japan. “Vital Care Network System”. 2002)

Research Grants
1. The Next Generation Software Project ofInformation-technology Promotion Agency, Japan.
“Vital Care Network System”. 2002. ¥128,000,000
2. JSPS Grants-in-aid for Scientific Research “The basic
research of electrolyzed water for clinical use”.
12470316 Basic Research (B)(2) 20002001.¥6,200,000
3. JSPS Grants-in-aid for Scientific Research “Intratissue
blood vessels detection using infrared for the aid of
minimum invasive surgery”. 13878179 Early Stage
Research. 2001-2002. ¥1,300,000
4. Grants-in-aid for Innovative Project of IndustryUniversity-Government Cooperation in Ministry of

Education, Culture, Sports, Science and Technology“The research for practical use of medical integral
videography” 2000-2003. ¥130,000,000
5. Tokyo Metropolis Grants-in-aid for IndustryUniversity-Government “Electrolyzed water for thebacterial wound healing” April 1999~Feb 2000.
¥6,569,000

Select Publications
1. Kitagawa H, Yamazaki T, Akiyama T, Yahagi N,
Kawada T, Mori H, Sunagawa K: Modulatory effects
of ketamine on catecholamine efflux from in vivo
cardiac sympathetic nerve ending in cats. Neurosci
Lett 24: 232-236; 2002
2. Kono M, Yahagi N, Kitahara M, Fujiwara Y, Sha M,
Ohmura A: Cardiac arrest associated with use of anargon beam coagulator during laparoscopic cholecyctectomy. Br J Anaesth 87: 644-646, 2001
3. Yahagi N, Kono M, Kitahara M, Fujiwara Y, Asakawa
Y, Katagiri J, Sha M, Ohmura A, Murakami A,
Takamoto S: Cause of airway obstruction during
cuffed oropharyngeal airway. Resuscitation 48: 275278, 2001
4. Yahagi N, Kono M, Kitahara M, Ohmura A, Sumita
O, Hashimoto T, Hori K, Ning-Juan C, Woodson P,
Kubota S, Murakami A, Takamoto S: Effect of electrolyzed waters on wound healing. Artif Organs 24:
984-987, 2000
5. Yahagi N, Matsui J, Matsui S, Amakata Y, Kumon K,
Ueda-Ishibashi H. Low molecular weight dextran
attenuates effects of oleic acid-induced lung injury inrats. Am J Emerg Med 18: 180-183, 2000
6. Yahagi N, Yamazaki T, Akiyama T: Either
desipramine or TMB-8 suppresses cyanide on
induced norepinephrine efflux from in vivo cardiac
sympathetic nerves of cats. Brain Research 864: 157161, 2000
7. Imanaka H, Nishimura M, Takeuchi M, Yahagi N,
Kumon K: Autotriggering due to cardiogenic oscillation during flow-triggering mechanical ventilation.
Crit Care Med 28: 402-407, 2000
8. Murakami A, Kaneko Y, Imanaka K, Takamoto S,
Yahagi N: Easy aortic cannulation: a tranxyphoidal
approach. Artif Organs 24: 156-157, 2000
9. Yahagi N, Shimizu R, Kono M, Kitahara M, Katagiri J,
Sha M, Ohmura A: Retractor to facilitate fiberscopeaided tracheal intubation. Resuscitation 41: 283-284,
1999
10. Kumon K, Yahagi N, Imanaka H, Takeuchi M,
Miyano H, Ohashi Y. Nitric oxide inhalation as achemical assist for the circulation in patients after
cardiac surgery. Artif Organs 23: 169-174, 1999
11. Yahagi N, Tanigami H, Watanabe Y, Kumon K:
Semiprone position relieved airway obstruction
resulting from dilated pulmonary artery. Ann Thorac
Surg 67: 894, 1999
12. Yahagi N, Kumon K, Tanigami H, Watanabe Y,
Haruna M, Hayashi H, Takamoto S. Cardiac surgery

295and inhaled nitric oxide: Indication and follow up.
Artif Organs 22: 886-891, 1998
13. Yahagi N, Kumon K, Watanabe Y, Tanigami H,
Haruna M, Hayashi H, Imanaka H, Takeuchi M,
Ohashi Y, Takamoto S: Value of mild hypothermia inpatients who have severe circulatory insufficiency
despite the use of IABP. J Clin Anesth 10: 120-125,
1998
14. Yahagi N, Akiyama T, Yamazaki T: Effect of omegaconotoxin GVIA on cardiac sympathetic nerve endings. J Autonom Nerv System 68: 43-48, 1998
15. Yahagi N, Watanabe Y, Kumon K: Ultrasound detection of diaphragmatic paralysis after cardiac surgery.
Ann Thorac Surg 65: 1841, 1998
16. Yahagi N: Invited commentary for “A randomized,
double-blind trial of inhaled nitric oxide in LVAD
recipients with pulmonary hypertension”. Ann
Thorac Surg 65: 345, 1998
17. Haruna M, Kumon K, Yahagi N, Watanabe Y: Blood
volume measurement at bed side using ICG pulse
spectrophotometry. Anesthesiology 89: 1322-1328,
1998
18. Kumon K, Yahagi N. Nitric oxide inhalation
increased oxygen delivery after cardiovascular surgery in adult patients whether or not they have pulmonary hypertension. J.Anesth 12: 180-184, 1998
19. Yamazaki T, Akiyama T, Kawada T, Kitagawa H,
Takauchi Y, Yahagi N, Sunagawa K: Norepinephrine
efflux evoked by potassium chloride in cat sympathetic nerves: dual mechanism of action. Brain Res
794: 146-150, 1998
20. Nakayama M, Kumon K, Yahagi N, Haruna M,
Watanabe Y, Hayashi H: Antiphospholipid antibody
syndrome in a case with redo coronary artery bypass
grafting under cardiopulmonary bypass. Surg Today
28: 423-426, 1998
21. Yahagi N, Kumon K, Tanigami H, Watanabe Y,
Haruna M, Matsui J: Helium/Oxygen breathing
improved hypoxemia after cardiac surgery. Artif
Organs 21: 24-27, 1997
22. Yahagi N, Kumon K, Watanabe Y, Tanigami H,
Haruna M, Hayashi H, Imanaka H, Takeuchi M,
Murakami A: Detection of tracheal stenosis bycineangiocardiography in patients with congenital
heart disease. Anesth Analg 85: 1180-1181, 1997
23. Matsui J, Yahagi N, Kumon K, Hayashi H, Watanabe
Y, Haruna M, Yagihara T, Takamoto S: Effect of
inhaled nitric oxide on postoperative pulmonary circulation in patients with congenital heart disease.
Artif Organs 21: 17-20, 1997
24. Tanigami H, Yahagi N, Kumon K, Watanabe Y,
Haruna M, Matsui J, Hayashi H: Long-term sedation
with isoflurane for patients after cardiac surgery.
Artif Organs 21: 21-23, 1997
25. Hayashi H, Kumon K, Yahagi N, Haruna M,
Watanabe Y, Matsui J, Hattori R: Successful treatment of mediastinitis after cardiaovascular surgery
using electrolyzed strong acid aqueous solution. Artif
Organs 21: 39-42, 1997

296

26. Yamazaki T, Kawada T, Akiyama T, Kitagawa H,
Takauchi Y, Yahagi N, Sunagawa K: Omega-conotoxin GVIA and desipramine insensitive norepinephrine
efflux from cardiac sympathetic nerve terminal.
Brain Res 761: 329-332, 1997
27. Murakami A, Fukahara K, Ichida F, Yahagi N,
Kumon K: Significance of nitric oxide inhalation forreperfused lung. Artif Organs 21: 83-84, 1997
28. Watanabe Y, Kumon K, Yahagi N, Haruna M,
Hayashi H, Matsui J: Use of a pulse dye-densitometry
ICG-test (indocyanine green clearance test) to evaluate liver cirrhosis before cardiac surgery. Comparison
with Child’s classification. World Congress Intensive
Crit Care Med 9: 94, 1997
29. Watanabe Y, Kumon K, Yahagi N, Haruna M,
Hayashi H, Matsui J: Assessment of hepatic function
using a pulse dye-densitometry ICG-test (indocyanine green clearance test): value in patients withdeteriorated liver function after cardiac surgery. 9thEuropean Congress on Intensive Care Medicine pp797-801, 1996
30. Yahagi N, Kumon K, Tanigami H, Watanabe Y,
Matsui J: Helium/Oxygen breathing improved
hypoxemia after cardiac surgery: Case reports.
Anesth Analg 80: 1042-1045, 1995
31. Yahagi N, Kumon K, Nakatani H, Matsui J, Sasako Y,
Isobe F, Sakakibara Y, Kitoh Y, Nagata S, Haruna M,
Watanabe Y, Takamoto S: Inhaled nitric oxide forthe management of acute right ventricular failure inpatients with a left ventricular assist system. Artif
Organs 19: 557-558, 1995
32. Yahagi N, Tanigami H, Watanabe Y, Kumon K: A
problem with an infant speaking tracheotomy tube
(Vocalaid”). Anaesthesia 50: 91-92, 1995
33. Yahagi N, Kumon K, Umemoto T, Shimura H,
Kawaguchi AT, Tanigami H, Miyashita K: Cyclic
decrease in mixed venous oxygen saturation for the
early diagnosis of seizure complications after cardiac
surgery. Anesth Analg 80: 404-407, 1995
34. Yahagi N, Kumon K, Tanigami H, Watanabe Y, Sato
T: A new, simple device for fixing orotracheal tubes.
Anaesthesia 49: 916, 1994
35. Yahagi N, Kumon K, Tanigami H, Watanabe Y,
Ishizaka T, Yamamoto F, Nishigaki K, Matsuki O,
Yagihara T: Inhaled nitric oxide for the postoperative
management of Fontan-type operation. Ann Thorac
Surg 57: 1371-1372, 1994
36. Yahagi N, Furuya H, Matsui J, Sai Y, Amakata Y,
Kumon K: Improvement of the left Boncho-Cath”
double lumen tube. Anesthesiology 81: 781-782,
1994
37. Yahagi N, Kumon K, Nakatani T, Ishikawa T,
Tanigami H, Eishi K, Takahashi S: Peripartum cardiomyopathy and tachycardia followed by multiple
organ failure. Anesth Analg 79: 581-582, 1994
38. Yahagi N, Tanigami H, Kumon K, Yamada K,
Takahashi O, Yagihara T: Tracheal granulations secondary to wall compression by endotracheal tubes in
infants. Can J Anaesth 41: 1123-1124, 1994

39. Yahagi N, Kumon K, Tanigami H: Bronchial lavage
with a fibreoptic bronchoscope via a laryngeal mask
airway in an infant. Anaesthesia 49: 450, 1994
40. Murakami A, Fukahara K, Uozaki Y, Ichida F,
Tsubata S, Yagihara T, Yahagi N. Three cases of left
ventricular outflow tract obstruction after intracardiac repair of congenital heart disease. Advanced
Cardio-Thoracic Surg , Axel Springer Japan
Publishing. pp11-4, 1994
41. Yahagi N, Kumon K, Sugimoto H, Inagaki Y: A use oftelescope of rigid type bronchoscope through endotracheal tube in infants. Anesth Analg 76: 207, 1993
42. Kumon K, Sugimoto H, Kitahara H, Yahagi N:
Application of recombinant human erythropoietin
for preoperative autologous blood banking on
patients undergoing cardiac surgery. Therapeutic
Plasmapheresis (Xll), pp 875-878, 1993
43. Inagaki Y, Kumon K, Sugimoto H, Yahagi N: A new
hemofiltration device with reversible roller pump forcorrecting volume controlled by a precise weight balancer. Therapeutic Plasmapheresis (Xll), pp 757-759,
1993
44. Yahagi N, Nishikawa A, Matsui S, Komoda Y, Sai Y,
Amakata Y: Pituitary apoplexy following cholecystectomy. Anaesthesia 47: 234-236, 1992
45. Yahagi N, Nishikawa A, Sai Y, Matsui J, Amakata Y:
Double aortic arch presenting as massive haematemesis after removal of a nasogastric tube. Can J
Anaesth 39: 894, 1992
46. Yahagi N, Furuya H, Sai Y, Amakata Y: Effect of
halothane, fentanyl, and ketamine on the thresholdfor transpulmonary passage of venous air emboli in
dogs. Anesth Analg 75: 720-723, 1992
47. Stuhmar W, Conti F, Suzuki H, Wang X, Noda M,
Yahagi N, Kubo H, Numa S: Structural parts involvedin activation and inactivation of the sodium channel.
Nature 339: 597-603, 1989
48. Suzuki h, Bechk S, Kayano T, Noda M, Kubo H,
Yahagi N, Numa S: Functional expression of cloned
cDNA encoding sodium channel lll. FEBS Letters
228: 195-200, 1987
49. Yahagi N, Furuya H: The effects of halothane andpentobarbital on the threshold of transpulmonary
passage of venous air emboli in dogs. Anesthesiology
67: 905-909, 1987
50. Yahagi N, Miyazaki M, Itoh Y: Cardiopulmonary
effect of halothane concentration on pulmonary circulation during air embolism in dogs. Resuscitation
13: 81-86, 1986

297