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[Hokkaido University]
Nagara Tamaki, Hiroki Shirato, Hirotoshi Akita, Yuji Kuge, Masayori Ishikawa, Chietsugu Kato,
Kikuo Umegaki, Tohru Shiga, Rikiya Onimaru, Kohsuke Kudo, Fujio Inage, Noriko Manabe,
Kazuhiko Tsuchiya, Ken-ichi Nishijima, Khin Khin Tha, Norio Katoh, Tetsuya Inoue, Fumi Kato,
Noriyuki Fujima, Rumiko Kinoshita, Taeko Matsuura, Seishin Takao, Ryusuke Suzuki, Nam Jin Min,
Yuichi Hirata, Koichi Yasuda, Eriko Suzuki, Kentaro Nishioka

[Hitachi, Ltd.]
Keiji Kobashi, Hisaaki Ochi, Takeshi Sakamoto, Kenichi Kawabata, Norihito Kuno, Shinichi Kojima,
Rika Baba, Hiroko Hanzawa, Toru Shirai, Atsurou Suzuki, Wataru Takeuchi, Kazuki Matsuzaki, Naomi Manri

[Mitsubishi Heavy Industries, Ltd.]
Katsuhisa Toyama, Akira Shibazaki, Shuji Kaneko, Kunio Takahashi, Takanobu Handa

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Achieving innovations in life science will require a system that firmly supports two-way data flows "from bench to bed" and "from bed to bench". Based on directions from the program headquarters and the steering committee, Advanced Medical Research Hub, including the Graduate School of Medicine and the university hospital, is taking a role in translational research by collaborating with other project hubs. The university hospital aims to become a center for more advanced medicine. This will be enabled 1) by creating a program that allows master's and doctoral students in the physical sciences, engineering and pharmaceutical science to participate in translational research and 2) by making the university hospital a facility that returns the achievement of this project to society. To become internationally dependable for clinical trials, the hub will promote collaboration with national and local networks for clinical trials and employment of clinical statisticians.
To realize its goals, the project hub has been revising its management system, conducting research under two central themes: that on individualized optimization of treatments for patients, and that on molecular tracking radiotherapy, and supporting translational researchs from innovation.

1) Research for appropriate treatment for patients

This project investigates development of molecular imaging for patient management. The molecular imaging permits precise assessment of pathophysiology which leads optimum treatment strategy of each patient. To facilitate this purpose, we have developed the first new semiconductor PET system for human brain imaging and semiconductor gamma camera using CdTe detectors. This new system provided higher resolution and higher contrast brain functional images with less scatter noise as compared to the current PET system. The basic and clinical studies indicated that this system permits precise assessment of cerebral glucose metabolism and also better identification of intratumoral inhomogeneity. Detection of such intratumoral inhomogeneity by a new PET system has a potential for pinpoint radiotherapy on a patient basis. On the other hand, high sensitivity is desirable for patient comfort. So the improved PET system which provides a 35% raise in sensitivity has been developed to accelerate clinical studies.
We also developed a prototype single photon emission tomography system using semiconductor detectors in order to promote the technology of semiconductor detectors. The prototype system was placed in Hokkaido University hospital and we are now investigating advantages of that camera. New collimation system was also developed and garnering praise.
Wide clinical applications of molecular imaging may require new developments of functional analysis using advanced imaging systems with suitable PET probes. Our research goal is new applications of molecular imaging for patient management by providing suitable molecular and functional information in vivo for optimal treatment strategy on patient basis. We have focused on (i) cancer detection and treatment strategy, (ii) early diagnosis of atherosclerosis, and (iii) pathophysiological assessment of refractory disorders.

  • PET画像1a
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(i) Cancer detection and treatment planning

FDG-PET studies have confirmed value of early assessment of treatment effect, as compared to the morphological imaging, such as X-ray CT. We investigate the improvement of capability of new molecular imaging for assessment and prediction of the treatment effect with use of high resolution PET and suitable molecular probes. This investigation may reduce the medical cost by early and optimal treatment with reducing futile therapy. A small sized cancer with mm size has 10 times higher radiosensitivity than a cancer with >1cm due to less hypoxic cells in small tumor. A high resolution semiconductor PET with suitable PET tracer to identify hypoxic tissues will enhance early detection of the cancer (<1 cm) and provide suitable treatment strategy in each patient based on the tumor characterization. Thus, molecular imaging using a suitable camera and probes has a great potential to provide best patient management, such as radiotherapy planning.


(ii) Early detection of atherosclerosis

Early detection of atherosclerosis has a potential for new application for preventive medicine, particularly for patients with high risk group based on genetic and past-history analysis. Early detection of intravascular vulnerable plaque by high resolution PET and molecular probes permits prevention of acute stroke or infarction by the early treatment of various medical or intravascular treatment. In addition, PET enables quantitative assessment of coronary endothelial dysfunction which seems to an early marker of atherosclerosis seen in most of the high risk patients, and therefore, this method may select high risk group who may require intensive therapy.

(iii) Pathophysiological assessment of refractory disorders

Molecular imaging has an important role to provide new insights into pathophysilogy of various refractory disorders. Of particular PET enables quantitative assessment of neurotransmission and receptor functions in vivo, which has a unique potential for identifying dysfunction in various neurodegenerative and neuropsychiatric disorders. We have developed new radioligand for quantitative assessment of beta-receptor density (Bmax) of the myocardium, and demonstrated reduction of Bmax in patients with severe heart failure. Those with severe Bmax reduction (beta-receptor down regulation) had a greater potential for improvement of cardiac function by beta-blocker therapy. Similar results may be expected in the neuronal disorders. Thus, precise assessment of neurotransmission and receptor function permits accurate diagnosis, its severity assessment, and optimal patient management on a patient basis, not disease basis.

2) Research on molecular tracking radiotherapy

This research aims at building the world's first high energy medical linear accelerator with an on-board positron emission tomography (PET) device dedicated for molecular image-guided radiation therapy (m-IGRT) and establishing a new technique for visualizing vital reactions in the human body which until now have been difficult to perform or thought to have not been possible.
In 2007, our research on "Four dimensional radiology with higher accuracy for organ motion" was given the Research Front Award in clinical medicine by Thomson Scientific which recognized our group as a pioneer in 4D-radiotherapy. Hokkaido University currently holds a patent for this technology.
We have introduced the basic technology in performing highly-accurate radiation therapy from precise diagnosis through accurate tumor region delineation during treatment planning by using morphologic images, such as CT or MRI, and functional image such as PET. The purpose of the system is not only to provide simple fusion of images, but also to enable the detection of quantitative changes in both morphology and physiology before and after therapy. Together with faster imaging systems, this technique can evolve into new methods for advanced medical treatment.
We also have an R&D center for the development of the first semiconductor PET and a pool of research staff working on advanced delivery of radiation therapy.

(i) Development of a molecular-imaging device for radiation therapy

In order to realize one of the goals of this project, which is to build the first molecular image-guided radiation therapy device, our immediate objective is to come up with a fundamental technology for a new PET device that can be physically interfaced and simultaneously used with a medical linear accelerator during treatment.
Standard patient set-up verification prior to the start their radiotherapy treatment are carried out by co-registering portal images and digitally reconstructed radiograph (DRR) generated from a treatment planning system. With this procedure, we can check whether that the tumor is appropriately located inside the irradiation field. However, radiography using high energy X-rays generate low contrast images, hence it is difficult to accurately recognize the tumor unless it is a solid mass with large enough volume. As an alternative, we propose to build a new PET device dedicated for the verification of patient setup by means of molecular imaging through tumor recognition using positron tomography.
The initial design for our m-IGRT device will make use of a parallel plane PET system similar to that shown in the figure below. According to our recent study, the parallel plane PET can have some limitations in terms of resolution towards the axis perpendicular to the PET detectors; however, this PET might have a better resolution than a conventional PET device at the plane parallel to the PET detectors. We confirmed from simulations that the resolution is high enough to delineate tumors locations in the order of millimeters allowing accurate patient setup verification based on tumor location just prior to treatment.
We have already developed a proto-type parallel plane PET device and succeeded in illustrating FDG positions by measuring coincidence annihilation gamma rays. At this time, the device does not yet have a sufficient field of view or a sufficient resolution for clinical use. Thus we are in the process of improving the detector array design and signal processing procedure to enlarge field of view and to achieve higher resolution. We also plan to conduct further research on the possible integration of the technology used in the real-time tumor tracking system (RTRT) developed at Hokkaido University and the small accelerator developed by Mitsubishi Heavy Industry Corp. in coming up with the first m-IGRT device.


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(ii) Dose escalation in radiation resistant hypoxic cell

The collaboration between the Photon-positron Research Hub and Hokkaido University Hospital has successfully used the FMISO in visualizing hypoxic regions in radiation resistant cancer tissues. Tumor delineation using FMISO has been used in IMRT planning head and neck cases. We now plan to apply this technology to tumors in the lung and other regions affected by organ motion for the implementation of a four-dimensional IMRT (4D-IMRT).

(iii) Research on a multi-dimensional image-guided radiation therapy

In the same collaborative work between the Photon-position Research Hub and Hokkaido University Hospital, better tumor delineation has been made possible with the development of the semi-conductor PET and the concurrent use of FDG and FMISO with it. With this diagnostic system we are able to determine the variation in tumor volume throughout the treatment and change the patient treatment plan accordingly. This adaptive approach to radiation therapy is one of the ways by which we can perform 4D-IMRT.

(iv) Research on radiation therapy focused on some factors that can be impossible for imaging

From the collaborative research between the Disease-related Protein Structure hub and the Drug Discovery Platform Hub, we have found out numerous important reactions in the living body, in relation to radiation therapy, that are not easily visualized through present imaging modalities. We have shown that radiation therapy induces tumor specific immune responses. Especially, we have found that tumor-specific cytotoxic T lymphocytes (CTL), which were induced in the draining lymph node and tumor tissue of tumor-bearing mice, play a crucial role for radiation-induced tumor-growth inhibition. Accordingly, a combined therapy of radiation with immunotherapy may augment the generation of tumor-specific CTL at the tumor site and induce a complete regression of the tumor, though radiotherapy alone did not exhibit such a pronounced therapeutic effect. In addition, we have been studied the molecular mechanisms of invasive recurrence following radiation therapy using three dimensional cell culture system. These studies may contribute to improve the efficacy of radiation therapy.
We are carrying out a clinical research for early diagnosis and estimation of prognosis of the intractable diseases of the central nervous system, using MRI. With recent improvements in MRI technology, high resolution diffusion tensor imaging of the cervical spinal cord has become possible with 3 Tesla MRI scanners (Fig). Following optimization of the imaging parameters, we acquired high resolution diffusion tensor imaging of the cervical spinal cord of the normal subjects; and developed a diffusion tensor image database of the normal human brain and cervical spinal cord. Currently, we are collecting the diffusion tensor images of the brain and cervical spinal cord of the patients with intractable diseases of the central nervous system. It is expected that, comparison of the diffusion tensor images between the patients and the age-and gender-matched normal subjects would allow visualization of lesions in the patients that are difficult to be detected by routine MRI techniques.



Coordinating Office, Future Drug Discovery and Medical Care Innovation Project
Kita 21, Nishi 10, Kita-ku, Sapporo, Hokkaido 001-0021, Japan
Tel: +81-(0)11-706-9188 Fax: +81-(0)11-706-9190

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