Main site: 10F
Keizo Saji Memorial Hall
Reception ( Welcome meeting ): 9F

Poster session & coffee : 4F (406)

Osaka University Nakanoshima Center
4-3-53 Nakanoshima, Kita-ku, Osaka 530-0005, Japan
Tel : +81-6-6444-2100
Fax : +81-6-6444-2338

Wireless network for guests
SSID : onc-ap
PASS : oncap178wh8ba

Program

1st day (19th March)
8:45 -The hall & the reception desk (at 10F lobby) opening

9:30 -

Opening address
Dr. Wolfgang Weiss (ex-UNSCEAR Chair)
Overview of this workshop
Dr. Yoshiharu Yonekura (ex- NIRS President, ex-UNSCEAR Chair)

9:45 - 11:45

Morning session
1.1. Dose and Dose-rate Effects
Chairperson: Dr. Ulrike Kulka (BfS)

1M01

Dose- and Dose-Rate Effects of Ionizing Radiation for Cancer Incidence andLife-Shortening.
Dr. Gayle Woloschak (Northwestern University)

1M02

Life span and tumorigenesis in mice exposed to continuous low dose-rate
gamma rays.
Dr. Ignacia Braga-Tanaka (Institute for Environmental Sciences)

1M03

How high can you go, radionuclide therapy is effective at low dose rate.
Dr. Mark Konijnenberg (Erasmus MC)

11:45 - 13:00
13:00 - 15:30

Lunch breakAfternoon session I
1.2. From Mutation to Cancer
Chairperson: Dr. Masako Bando (Kyoto University, Osaka University)

1A11

Overview: The divergence of approaches from molecular biology and macrolevel.
Dr. Masako Bando (Kyoto University, Osaka University)



1A12

Responses to low dose radiation in vivo: DNA damage, aging, and immune
regulation.
Dr. Yi Wang (CNL)

1A13

Dose-rate effects of lymphocyte chromosome aberrations in chronically
irradiated mice after age adjustment.
Dr. Kimio Tanaka (Institute for Environmental Sciences)

1A14

WAM model - a dynamic equilibrium model for the dose-rate effect.
Dr. Yuichi Tsunoyama (Kyoto University)

Panel discussion“Overcome the divergence of approaches of molecularbiology from macro level.”

15:30 - 16:00
16:00 - 18:00

Coffee breakAfternoon session II
1.3. Activities of the Consortium for Medicine, Chemistry and Physics at
Osaka University
Chairperson: Dr. Atsushi Shinohara (Osaka University)

Opening
Dr. Atsushi Shinohara (Graduate School of Science, Osaka Univ.)

16:05 - 16:20
1A21

Medicine and science collaborative research for targeted alpha therapy inOsaka University.
Dr. Koichi Fukase (Graduate School of Science, Osaka Univ.)

16:20 - 16:45
1A22

Production and isolation of At-211 for targeted alpha therapy at Osaka
University.
Dr. Zijian Zhang (Graduate School of Science, Osaka Univ.)

16:45 - 17:10
1A23
17:10 - 17:35
1A24
17:35 - 18:00
1A25

Radiolabeling of small molecules with astatine(211At) for theranostics.
Dr. Yoshifumi Shirakami (Graduate School of Medicine, Osaka Univ.)
Preparation of novel anticancer drugs using At-211.
Dr. Kazuya Kabayama (Graduate School of Science, Osaka Univ.)
Imaging of the targeted alpha therapy for the clinical application.
Dr. Tadashi Watabe (Graduate School of Medicine, Osaka Univ.)2nd day (20th March)
9:00 - 11:30

Morning session
2.1. Medical Database
Chairperson: Dr. Nobuyuki Osakabe (Hitachi, Ltd.)

2M01

Biomarkers and radiation therapy for patients with head and neck cancer.
Dr. Pierre Saintigny (Cancer Research Centre of Lyon)

2M02

Present status of patient dose in large part of the world.
Dr. Madan Rehani (MGH, HMS/IAEA)

2M03

Millennial medical record project - Toward establishment of authentic
Japanese version EHR and secondary use of medical data –Dr. Hiroyuki Yoshihara (Kyoto University, University of Miyazaki)

Panel discussion “How can medical database be effectively used in the BER
study and practice?”
Panelist: Dr. Nobuyuki Osakabe (Hitachi, Ltd.) & all speakers

11:30 - 13:00
13:00 - 15:00

Lunch breakAfternoon session I
2.2. Imaging Techniques for Radiotherapy and Cancer diagnosis(Big data and diagnosis, treatment)
Chairperson: Dr. Jun’ichi Kotoku (Teikyo University)

2A11

Potentials of Radiomics in Cancer Treatment.
Dr. Hidetaka Arimura (Kyushu University)

2A12

Imaging database and radiomics.
Dr. Akihiro Haga (Tokushima University)

2A13

Radiomics on MRI field.
Dr. Koji Sakai (Kyoto Prefectural University of Medicine)15:00 - 15:30
15:30 - 17:30

Coffee breakAfternoon session II
2.3. Radiation Biology and Medical Use
Chairperson: Dr. Akihiro Haga (Tokushima University)

2A21

Contribution of biological analysis platform to optimize the medical use ofionizing radiation.
Dr. Ulrike Kulka (BfS)

2A22

Quantitative personalized oncology - Mathematical models for precision
radiotherapy.
Dr. Heiko Enderling (Moffitt Cancer Center)

2A23

Medical radiation protection research strategies in Europe and the role of the
medical physicist in Europe.
Dr. Christoph Hoeschen (Otto-von-Guericke University)

18:00 - 19:30

Poster session

Room No.406 (4F)

19:30 - 21:30

Reception (Welcome meeting)Salon (9F)

3rd day (21st March)
9:00 - 11:30

Morning Session
3.1. Presidential Session: International Cooperation in Biological Effectsof Radiation
Chairperson: Dr. Yoshiharu Yonekura (ex-UNSCEAR Chair)

3M01

Understanding low dose radiation exposure effects : MELODI’s views on
developing international cooperation.
Dr. Jacques Repussard (MELODI)

3M02

Electric Power Research Institute International Dose Effect Alliance.
Dr. Donald A. Cool (EPRI, IDEA)

3M03

Low-Dose Radiobiology Program at Canadian Nuclear Laboratories: Past,
Present and Future.
Dr. Dmitry Klokov (CNL)

3M04

Planning and Acting Network for Low Dose Radiation Research (PLANET) andpromotion for integrated network in Japan.
Dr. Yutaka Yamada / Dr. Yoshiya Shimada (QST, PLANET)

3M05

JSPS committee “multidisciplinary research on the biological effects ofradiation”.
Dr. Takahiro Wada (JSPS committee)

Short talks on each organization / panel discussions

11:30 - 13:00
13:00 - 15:00

Lunch breakAfternoon session I
3.2. Radiation Protection in Medicine
3.2.1. Radiation induced cancer
Chairperson: Dr. Yoshiya Shimada (QST)



3A11

Radiation protection in therapy with radiopharmaceuticals.
Dr. Makoto Hosono (Kindai University)

3A12

Experimental evaluation of the carcinogenic effect of carbon ions and neutrons
in children.
Dr. Tatsuhiko Imaoka (NIRS, QST)

3A13

Second cancer after radiotherapy.
Dr. Jean-Marc Cosset (Amethyst Group, former ICRP C3 member)

15:00 - 15:30
15:30 - 17:30

Coffee breakAfternoon session II
3.2.2. New medical equipment for less radiation dose
Chairperson: Dr. Makoto Hosono (Kindai University)

3A21

Cancer risk from paediatric CT scanning.
Dr. Elisabeth Cardis (Institut de Salut Global de Barcelona)

3A22

Low-dose CT screening for lung cancer.
Dr. Takeshi Nawa (Hitachi General Hospital)

3A23

Development of low dose diagnostic CT.
Dr. Takashi Tanaka (Canon Medical Systems)

17:30 - 17:45

Closing Remarks

Abstracts of Oral Presentations

1M01
Dose- and Dose-Rate Effects of Ionizing Radiation for Cancer Incidence and Life-Shortening
Gayle E Woloschak, Tatjana Paunesku, Ben Haley, Alia Zander
Northwestern University School of Medicine, Chicago IL 60611
Effects of radiation on living organisms are numerous, with significant differences depending on total
radiation dose, dose rate etc. Nevertheless, there is a custom in the radiation protection to try todescribe all of the radiation effects with a linear non-threshold (LNT) model. The most recent BEIR VII
report depended on LNT model was subjected to many subsequent criticisms. For example, in an
exchange of opinions between Crowley and others and Calabrese and O'Connor in 2015 (Crowley et al
Radiat Res. 2015 Apr;183(4):476-81.) BEIR VII approach to calculation of dose and dose rate
effectiveness factor (DDREF) was criticized and the authors showed how different the same collection ofdata (specifically from table 4 from Preston et al. Radiat Res 2007; 168:1–64) looks when plotted aslinear or semi-logarithmic plots. Nevertheless, LNT model is still used for radiation protection. However,despite the use of this model most regulations of worker exposures also place a significant emphasis on
limiting possible radiation damage for given time period. For example, astronauts have prescribedmaximal monthly, yearly and career exposures (Nelson. Radiat Res. 2016 Apr;185(4):349-58). Thus,
radiation protection policies implicitly rely on understanding that biological aspects of radiation risk
depend on radiation delivery over time, even though dose protraction is not one of the questions
included in the LNT model.
Recent work from our laboratory (Haley et al. PLoS One. 2015 Dec 9;10(12):e0140989; Paunesku et al.
Int J Radiat Biol. 2017 Oct;93(10):1056-1063) considered ways in which BEIR VII evaluation of DDREF
disregarded much of the animal radiation data and made a direct comparison between animals exposed
to protracted or fractionated vs. acute radiation exposures. As shown in Figure 1 (replicated from
Paunesku et al. Int J Radiat Biol. 2017 Oct;93(10):1056-1063) a direct comparison of acute andprotracted radiation exposures up to 1.5 Gy using linear-liner model has a better goodness of fit than acomparison that uses linear-quadratic model.
It is probable that the focus on LNT model in radiation biology is one of the core problems in low dose
research, not so much because this model is flawed, but because the very notion that that type of model
may explain effects of radiation is wrong. In essence, all such studies assume that the probability that
one cell of a multicellular organism will acquire multiple mutations transforming it into cancer isequivalent to induction of a single lethal chromosomal aberration in a single cell in cell culture. A clear
contrast between these two statements should tell us that we are not modeling what should bemodelled. Our computational powers are increasing and yet we still insist on testing different types ofregression analyses using the data that is clearly too variable to be described by any one single curve.
We propose that is possible to envision new ways of modeling that would synergize with animal
research and capitalize on biological variation as the long established and the most fruitful source of all
biological knowledge. Just as any wet bench scientist knows that it is not possible to obtain good data
without positive and negative controls, new computational approaches can be envisioned that would try
to include a portion of the data that is deliberately selected to be “skewed” and where the test data are
expected to fall within or outside of certain expected domain. Using animal models one can not only do
experiments with positive and negative controls but also try to produce predictive models. “New”
modeling of cancer as an outcome of radiation damage could focus on volume of specific type of DNA

damage per cell, the likelihood of engagement of a given DNA repair mechanism or conversely, thelikelihood of its failure.

Figure 1. Life-shortening data from mice
exposed to acute and protracted
radiation up to 1.5 Gy total dose,
following BEIR VII procedure (for moredetails see Haley et al. 2015); currently
used model based on linear-quadratic
formula and alternative linear-linear
model comparisons. Comparison ofpredicted life-shortening fromprotracted radiation exposures in a 0–
1.5 Gy total dose range when only acuteanimal irradiation data on life-shortening
is used to calculate DDREF (dotted redline) vs. when both acute and protracted
data are compared (full lines) (a). In bothcases calculations are based on BEIR VII
approach, however, in one case (dotted
red line) the graph is based on acuteexposures, similar to extrapolations
done from A-bomb survivor data. In theother case, calculation is done
considering both acute and protracted
dose exposures; and the graph of lifeshortening associated with protracted
exposures is shown by a full red line.
Moreover, a simpler liner-linear model
provides a better fit with the data thanthe currently used linear-quadraticmodel. The Akaike Information Criteria(AIC) estimates appear above each fit
and quantify the goodness of fit: a lower
value indicates a better fit. Overall AIC
value for linear-quadratic model (-749)(b) is greater than the AIC value for linerlinear model (-765) (c), indicating thatthe linear-linear model fits the data (from Paunesku et al. Int J Radiat Biol. 2017 Oct;93(10):1056-1063.).

1M02
Life span and tumorigenesis in mice exposed to continuous low dose-rate gamma rays
Ignacia TANAKA
Department of Radiobiology, Institute for Environmental Sciences
Abstract
Late effects of low-dose and low-dose-rates of ionizing radiation are potential hazards to radiation
workers and to the general public, and have become a serious concern in the recent years, and evenmore so after the Fukushima accident. Our institute has been studying the late effects of continuous
low dose-rate radiation exposure in mice for over 20 years.
In 2002, we completed life span study using 4000 male and female 8-week-old specific pathogen
free (SPF) B6C3F1 mice. The irradiated groups were exposed to 137Cs gamma rays at dose-rates of 21,
1.1 and 0.05 mGy/day for approximately 400 days with total accumulated doses equivalent to 8000,
400 and 20 mGy, respectively. All mice were kept under SPF conditions until natural death andpathological examination was performed to determine the cause of death. Statistical analyses showedthat the life spans of mice of both sexes irradiated with 21 mGy/day (total dose = 8 000 mGy) and offemales irradiated with 1.1 mGy/day (total dose = 400 mGy) were significantly shorter than the
non-irradiated control group. The life spans, tumor incidence and tumor spectra in mice exposed to
0.05 mGy/day (a total dose of 20 mGy) was not significantly different from the non-irradiated control
group. Life shortening was attributed to premature death due to various types of neoplasms including
malignant lymphomas. In addition, significant increases in the incidence of hemangiosarcomas, liver,lung, adrenal, ovary and Harderian gland neoplasms were observed in mice exposed to 21 mGy/day.
These results suggested that continuous exposure to low-dose-rate gamma-rays for long periods causes
either early onset or increased progression of neoplasms.
To clarify whether life shortening was due to shortened tumor latency (early onset) or increased
tumor progression, 8 week-old SPF female B6C3F1 mice were exposed to 20 mGy/day for 400 days.
On the day 100 of irradiation, 60-90 mice were sacrificed, and every 100 days thereafter up to day 700(300 days after completion of irradiation), alongside age-matched non-irradiated controls. Pathologicalexamination was performed on all mice to identify lesions, as in the life span study. Completed lastyear

results show that increased incidences with no shortening of latency periods for malignant

lymphoma, hepatocellular adenomas/carcinomas, bronchiolo-alveolar adenomas and Harderian glandadenomas/adenocarcinomas in irradiated mice. Increased incidence with shortened latencies foradrenal subcapsular cell adenomas, ovarian were observed in the irradiated mice. The results show that
continuous exposure to low dose-rate gamma rays in female B6C3F1 mice caused both cancer
induction (shortened latency) and promotion/progression (early death), depending on the neoplasm sorgan/tissue of origin.
Recently, we completed the experimental phase of a transgeneration study using C57BL6 males
exposed to continuous low dose-rates similar to the life span study. After completion of the 400 day

exposure, the males were bred to non-irradiated 8-week-old virgin C57BL6 females to produce F1
mice. Randomly selected F1 were bred to produce F2. All the mice except the dams of F1 mice were
kept until natural death and were subjected to pathological examination.

Although there was no

significant difference in the pregnancy (F0) and weaning rates (F1) between the irradiated andnon-irradiated groups, litters from sires exposed to 20 mGy/day had significantly decreased mean litter
size and mean number of pups weaned.

Lifespans of sires (F0) exposed to 20 mGy/day and theirmale progenies (F1) were significantly shorter than the non-irradiated controls. Pathologicalexamination are still in progress.
The studies were performed under contract with the Aomori Prefectural Government, Japan.

1M03
How high can you go, radionuclide therapy is effective at low dose rate.
Mark Konijnenberg

Dept. Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands

Therapy with radionuclides have been very successful in the treatment of various diseases
depending on the specific uptake of the radionuclide or vector-drug it is labelled to. Thyroid
disorders and metastasized thyroid cancer can be treated with 131I as iodide is taken up by the
thyroid follicular cells through the sodium/iodide symporter (NIS) protein. Metastatic neuroendrine
tumours (NET) are successfully treated with 177Lu-DOTA-octreotate, with targeting by thesomatostatin analog peptide octreotate to somatostatin –receptor expressing lesions. Liver cancer
therapy is applied with intra-arterial administration of 90Y and 166Ho labelled microspheres, which gettrapped in the small vascular branches around liver tumour lesions. Still experimental, but very
promising is 177Lu PSMA for therapy of advanced (metastasized) stage prostate cancer , where PSMA
(prostate specific membrane antigen) is the targeting vector as this cell membrane protein is
upregulated in prostate cancer.
These radionuclide therapies deliver absorbed doses at a low dose rate according to an exponential
decay pattern, determined by both physical decay of the radionuclide and the clearance rate of theradiopharmaceutical. Systemic drug delivery makes that also physiological organs will be taking up
radionuclides and irradiated besides the specific uptake in organs and tumour lesions. In peptide
receptor radionuclide therapy (PRRT) off target uptake and radiation will occur in the kidneys byphysiological clearance of the radiopeptide in the circulation. In the radio-embolisation therapy offtarget radiation exposure will occur in healthy liver tissue surrounding the targeted tumour lesions.
Radionuclide therapy therefore requires patient-specific dosimetry for treatment planning to obtainsafe absorbed doses to normal tissues and efficacious absorbed doses in tumours.
Our department (Erasmus MC, Rotterdam, Netherlands) pioneered development of this therapy andrecently finalized phase III clinical trials with a fixed activity administration schedule of 4 x 7.4 GBq,.
This trial lead to favourable outcomes (increase of progression-free survival and life quality). Most
patients will, however, demonstrate relapse of the disease after PRRT with limited treatment options
left. Salvage retreatment with 2 x 7.4 GBq is offered to these patients. Possibly relapse can beprevented by administering higher doses or more cycles of activity to enhance the probability of acomplete cure. Simply administering a higher dose will leads to unacceptable healthy tissue damage,especially in the bone marrow (due to circulation) and kidneys (due to clearance and reabsorption) .
Response of tissue is not well known at the low to very low dose rates involved (initially in the orderof 0.05 - 0.25 Gy/h). Knowledge of the dose-effect curves at very low dose rates is of great
importance to design dosimetry guided treatment planning for PRRT.
Repair of sub-lethal damage will occur during the absorbed dose delivery and by this counteract thecytotoxic effects for the radiation. A dose-response curve was found in PRRT with 90Y-DOTAoctreotide for the occurrence of late (> 1 year after the last therapy cycle) toxicity in the kidneys. The
absorbed dose to the kidneys did not indicate a correlation with the induction of late renal toxicity,
but the Biologically Effective Dose (BED) derived from the Linear-Quadratic (LQ) model did. The
absorbed dose limits for PRRT are higher than the known dose-constraints for external beam therapy.
This increase is associated with the increased repair of sub-lethal DNA damage during the dosedelivery at low dose rate with PRRT. Also spatial heterogeneities in activity and absorbed dose
influence the dose response, mainly caused by the specific radiopharmaceutical uptake and therange of the emitted particles in relation to the distance from decay site to the functional units
defining the organ’s performance status.

According to the LQ model the BED as a function of time T can be defined as:
𝐵𝐸𝐷𝑇=𝐷𝑇+𝐺𝑇𝛼𝛽𝐷2(𝑇),with D(T) the absorbed dose and α/β the ratio between the linear and the quadratic radiation
sensitivity parameter. BED indicates the exponential relation with the surviving fraction offunctioning cells with the factor α. The Lea-Catcheside factor G(T) expresses the accumulation of
unrepaired DNA damage into lethal damage combinations during the dose the dose delivery and it isdefined as:
𝐺𝑇=2𝐷2𝑇0𝑇𝐷𝑡0𝑡𝐷𝑡′𝜑𝑡−𝑡′𝑑𝑡′ 𝑑𝑡
with 𝐷(t) the absorbed-dose rate as function of time and ϕ(t) the repair function in effect during theinterval between t’ and t and usually assumed to be a single-exponential process with repair half-life
Trep, and rate constant μ = ln⁡(2)𝑇𝑟𝑒𝑝 . If also the dose build-up proceeds according to a singleexponential curve with time and (effective) decay constant λ = ln⁡(2)𝑇𝑒𝑓𝑓, G(T) simplifies in the limit
T →∞ to: lim𝑇→∞𝐺𝑇=𝜆𝜆+𝜇=𝑇𝑟𝑒𝑝𝑇𝑟𝑒𝑝+𝑇𝑒𝑓𝑓. In the case of a dose D given in fractionated externalbeam radiotherapy with fractions of d : 𝐵𝐸𝐷=𝐷1+𝑑𝛼𝛽.
BED is commonly used in external-beam radiotherapy and brachytherapy to convert between
different fractionation schemes. In radionuclide therapy the relationship between BED and theincidence of renal complications after 90Y-DOTA-octreotide was comparable to that obtained forexternal-beam radiotherapy. Surprisingly the LQ model seems also to be valid at the very low dose
rates in radionuclide therapy. The LQ model parameters are semi-empirically determined for kidneys
and liver. For toxicity in other organs at risk after radionuclide therapies as the salivary glands(especially in PSMA therapy) these values are not known.
The LQ model parameters for tumour response after radionuclide exposure are not well known at all.
In analogy to high dose rate radiotherapy is the α/β ratio most probably higher than in normalorgans. Dose effect curves for tumour response after both 90Y as 177Lu PRRT indicate that doses of >200 Gy are needed to induce size reduction. Absorbed doses needed by beta-emitters to reduce
small (sub clinical) metastatic lesions are not well known. High LET radiation by alpha-particle
emitters is considered to optimize therapeutic effects in these small lesions. Preclinical research is
performed to determine the possible enhancement by alpha-emitters.
MIRD pamphlet 20, J Nucl Med 2008; 49:1884–1899
J Strosberg et al., N Engl J Med 2017;376:125-35
L Strigari et al., Eur J Nucl Med Mol Imaging. 2014;41:1976-88
E Ilan et al., J Nucl Med 2015; 56:177–182

1A11
Overview: The divergence of approaches from molecular biology and macro level.
Masako Bando
Yukawa Institute for Theoretical Physics, Kyoto University / Research Center for Nuclear Physics (RCNP), Osaka University

Micro Macroto

Radiationinducedeffects
BER2018(2018/3/19-21 )3/19 Afternoon session I
13:00 - 15:30

Masako Bando

30 min (talk) + 5 min (short Q&A)
Responses to low dose radiation in vivo: DNA damage, aging, andimmune regulation. : Dr. Yi Wang (CNL)
Dose-rate effects of lymphocyte chromosome aberrations
in chronically irradiated mice after age adjustment.
Dr. Kimio Tanaka (Institute for Environmental Sciences)
A dynamic equilibrium model for the dose-rate effect.
Dr. Yuichi Tsunoyama (Kyoto University)

Micro to Macro

Panel discussion“Overcome the divergence of approaches”
with the speakers of morning session
Radiation effects from the results of animal experiments.
Dr. Gayle Woloschak (Northwestern University)
Life span and tumorigenesis in mice exposed to continuous
low dose-rate gamma rays.
Dr. Ignacia Tanaka (Institute for Environmental Sciences)
How high can you go, radionuclide therapy is effective
at low dose rate.: Dr. Mark Konijnenberg (Erasmus MC)

why?

overview
2

Evolusion

Micro to Macrouniverse

Elementary particle

DNA

Biologicl organizm
human

Global scope
mechanizm

4societyconnecting
global structure
to micro mechanism

Divergence
to Universal Understanding
Across species
Human nice Drosophila

LNT LQM?

Quality from quality
mathematical tools needed56Micro to Macro     

micro


   
DNA damage & mutation 7micro  Germ cell   

Somatic cell
animal experiments
Dr. G. Woloschak
Dr. Yi Wang (CNL)
Dr. K. Tanaka
Dr. I. Tanaka
Dr. Yi Wang (CNL).

Thermalinstability

ROS

ROS
Replication
error

Directheredity
evolution   
Damage control system?? Complicatedmany steps withvariety of effects

Directly observedin F1 or F2

Immune control system DDREF      

 animal experiments
Muller & Russel
Dr. Y. Tsunoyama

LNT?



scaling
Human
Mice
DrosophilaLet’s havehotinterdisciplinary
discussions!

EDR

Doubling dose

11

12



1A12
File No: CW-121110-002-000

Abstract2017 Dec 08

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Responses to low dose radiation in vivo: DNA damage, aging, and immune regulation
Yi Wang*, Youssef Ismail, Dmitry Klokov
Canadian Nuclear Laboratories, Chalk River, Ontario, Canada

Biological and health effects of low doses of radiation (LDR) are extensively studied and debated by bothexperimental and epidemiological research. The Linear No-Threshold (LNT) hypothesis, assuming that all
doses increase the risk of cancer, birth defects, and heritable mutations, is currently used in all radiation
protection practices. Although the LNT hypothesis is a simple and convenient method to optimize
procedures and regulations in radiation protection, its usage remains controversial. LNT hypothesis ismajorly supported by the Atomic Bomb Survivor studies (1, 2), however, many recent studies suggestthat the responses per unit dose at low doses cannot be predicted by linear extrapolation of responses
observed per unit dose at high doses (3). Earlier research from our laboratories found that the LDR
prolongs the latency of high dose radiation-induced myeloid leukemia in CBA/H mice (4). It also
increases the latency of spontaneous lymphomas and spinal osteosarcomas (5), or high dose radiationinduced cancers in cancer-prone, radiation-sensitive Trp53(+/-) heterozygous mice (6). Our data suggestthat a single, low, whole body dose (less than 100 mGy) of radiation increases cancer latency andconsequently prolongs the lifespan in both wild-type and cancer-prone mice. The results demonstratethat the assumption of a linear increase in risk with increasing dose in vivo is not warranted and LDR
actually has beneficial effects (Radiation Hormesis model). However, this systemic radio-adaptive andradio-protective responses remain unexplained mechanistically.

Because the increased genomic instability is a hallmark of cancer (7) and loss of function mutations oralteration in DNA repair genes expression are extensively associated with cancer development andprogression, we first investigated whether LDR in vivo was capable of enhancing DNA double-strand
break (DSB) repair in lymphoid tissues of C57Bl/6J mice. Our data demonstrate that in vivo LDR did notaffect the rate of rejoining of DNA DSBs in splenic and thymic lymphocytes challenged in vitro with ahigh dose of 2 Gy radiation (8). The screen of the expression of a panel of 84 DNA repair genes revealed
that base and nucleotide excision repair genes such as APEX2, DDB1, and XPD are predominantly
upregulated in response to a challenging 2 Gy irradiation in mice that were pre-exposed to low priming
doses of 20 and 100 mGy compared with mice that were exposed to 2 Gy only. Using a DNA repairfunctional assay, we demonstrated that recognition and repair of 8-oxoG in plasmid DNA, accomplishedby base excision repair, is enhanced in nuclear extracts prepared from the spleens of mice irradiatedFile No: CW-121110-002-000

Abstract2017 Dec 08

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with low doses and a 2 Gy challenging dose compared with 2 Gy only. Our results indicate that DNA
excision repair may be responsible for the suppression of tumorigenesis in LDR induced mice.

Aging has been defined as a progressive decline of organ function, with loss of homeostasis andincreasing probability of illness and death (9), and accumulation of age-related DNA damage plays asignificant role in aging. Much of the evidence relevant to radiation effects on aging and longevity has
been obtained for high doses, whereas the effects of LDR on longevity are very limited and inconsistent.
We examined the effect of LDR on aging in mice in vivo and found that a single dose of gamma-radiationof 100mGy at delivered at 13 months of age significantly reduced the expression of senescenceassociated β-galactosidase in the kidney of 26-month old mice. We also studied the effects of LDR on
the immune system of aged mice. Our data indicate that, unlike their young counterparts, LDR delivered
to aged mice rejuvenates their immune system as demonstrated by the replenishment of the cytokine
profile in plasma, the boost of the colony formation and the activation of the signal transduction
proteins in hematopoietic stem cells, the increase of DNA damage and the decrease of cell number inblood mononuclear cells. Overall, our results suggest that LDR evokes a spectrum of molecular, cellularand systemic tissue responses in vivo to maintain the balance between cell damage and adaptive cell
protection. Therefore, radiation hormesis and/or threshold models might be useful in future radiation
protection practices.

References
1.
2.
3.
4.
5.
6.
7.
8.
9.

E. J. Grant et al., Radiat Res 187, 513 (May, 2017).
K. Ozasa et al., Radiat Res 177, 229 (Mar, 2012).
E. J. Calabrese, Dose Response 15, 1559325817735478 (Oct-Dec, 2017).
R. E. Mitchel, J. S. Jackson, R. A. McCann, D. R. Boreham, Radiat Res 152, 273 (Sep, 1999).
R. E. Mitchel, J. S. Jackson, D. P. Morrison, S. M. Carlisle, Radiat Res 159, 320 (Mar, 2003).
R. E. Mitchel, J. S. Jackson, S. M. Carlisle, Radiat Res 162, 20 (Jul, 2004).
D. Hanahan, R. A. Weinberg, Cell 144, 646 (Mar 4, 2011).
M. S. Blimkie, L. C. Fung, E. S. Petoukhov, C. Girard, D. Klokov, Radiat Res 181, 548 (May, 2014).
B. Schumacher, G. A. Garinis, J. H. Hoeijmakers, Trends Genet 24, 77 (Feb, 2008).

1A13

Dose-Rate Effects of Lymphocyte Chromosome Aberrations in Chronically
Irradiated Mice after Age Adjustment
Kimio Tanaka1, Atsushi Kohda1, Kenichi Satoh2
1.
Institute for Environmental Sciences, 2. Res. Inst. Radiation Biology & Medicine,
Hiroshima University
Late effects of very low-dose-rate (LDRs) of ionizing radiation at low-dose range
has become serious concern to radiation workers and general public in recent years.
However, there is almost no report on the relationship between biological effects andtotal exposure dose in the chronic exposure at very LDR. So far, many studies haveinvestigated dose and dose-rate effects have been investigated within the LDR andmedium-dose-rate (MDR) ranges (Lyon and Morris 1969, Russell and Kelly 1982;
Tucker et al. 1998; Sorensen et al. 2000; Ina et al. 2005). LDR and MDR are defined as
6 mGy/h (132 mGy/22h/day) or less and 6 mGy/h-5.94 Gy/h, respectively (UNSCEAR
2010). The Institute for Environmental Sciences (IES) has a unique facility designed tocontinuously exposed mice under specific pathogen free conditions to 137Cs-gamma
rays at three different dose-rates [0.05 mGy/22h/day(0.0023 mGy/h; abbreviated as 0.05
mGy/day hereafter), 1 mGy for 22 h/day (0.045 mGy/h; abbreviated as 1 mGy/day) and
20 mGy for 22 h/day (0.91 mGy/h; abbreviated as 20 mGy/day)], equivalent to photon(γ-ray) levels about 20, 400 and 8000 times higher than natural background radiation,
respectively. The dose-rate of 1 mGy/day is corresponding to that of daily dose ofcosmetic radiation in space. Lowest dose-rate of 0.05 mGy/day corresponds to that of
the annual mean limiting dose for radiation facility workers and also the mean daily air
dose measured in the government designated evacuation zone in Fukushima Prefecture
after the Fukushima Dai-ichi nuclear power plant accident. The endpoints have included
life span, cancer incidence, non-neoplastic disease, genetic effects and oncogene
alterations, chromosome aberrations, mutations, gene expression and cellular and tissue
responses.
Dose response and dose-rate effects at LDR range of frequencies of chromosome
aberrations in spleen lymphocytes in chronically irradiated mice from 56 age at thesethree different dose-rates were analyzed at each point for up 25 to 700 days, respectively.
Non-irradiated age matched control mice were also observed. Spleen lymphocytes were
stimulated with ConA, LPS and 4ME and cultured for 46 h to obtain metaphases.
Frequencies of chromosome aberrations of dicentrics and translocations detected by

FISH using centromere prove and M-FISH method, respectively, increased almost in
linear with irradiation dose in the dose rates of 1 mGy/day and 20 mGy/day, althoughthose of 0.05 mGy/day were not statistically significant. The α coefficient for linear
quadratic model (Y= βD2+αD+c、where Y is frequency of chromosome aberrations andD is irradiation dose in mGy) was obtained over a radiation dose-rate range of 1
mGy/day to 20 mGy/day in dicentrics and translocations decreased significantly with
reduction of dose-rate, after calculations with adjusting age using multiple linear
regression analysis, which is indicating that there is clear dose–rate effects within the
LDR range.
The results also indicate that the formula , 1+(β/α)D, for calculation of dose anddose-rate effectiveness (DDREF) based on the DNA repair model recommended by
ICRP 1991 is not appropriate. Therefore we obtained DDREF simply as the ratio of
HDR (890 mGy/min) to LDR (20 mGy/day) using formula of (βD2+α1D)/α2D.
Dose-rate effectiveness (DREF) for dicentrics and translocations at low-dose of 100
mGy were calculated as 4.5 and 2.3, respectively. An attempt to calculate DREF using
two parameters for induction of mutations in spleen and liver of gpt delta mice exposedto acute and low dose rate (20 mGy/day)(Okudaira et al 2010). Mutations rates of liver
as well as spleen of each mouse in the same group including controls were plotted on
X-axis for liver and Y-axis for spleen with the same axes scales. After values fromage-matched control mice were subtracted, DREF was obtained as 2.43. Organs
collaborate each other and such holistic approach will need in future. These studies will
be useful for radiation risk assessment and radiation protection. This study was
performed under contract with the Aomori Prefectural Government, Japan.

1A14
WAM model - a dynamic equilibrium model for the dose-rate effect
†

‡

§

§§

*

Yuichi Tsunoyama , Kazuyo Suzuki , Miwako Masugi-Tokita , Hiroo Nakajima , Yuichiro Manabe ,*****Takahiro Wada , Masako Bando†

Department of Biology, Radioisotope Research Center, Kyoto University‡

Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine Kyoto University§

Department of Urology, Shiga University of Medical Science§§*

Department of Radiation Biology and Medical Genetics, Graduate School of Medicine, Osaka University

Division of Sustainable Energy and Environmental Engineering, Graduate School of Engineering, Osaka University**

Department of Pure and Applied Physics, Kansai University***

Yukawa Institute for Theoretical Physics, Kyoto University***

Research Center for Nuclear Physics (RCNP), Osaka University

After the Fukushima Daiichi Nuclear Power Plant disaster, a research group of Japanesetheoretical physicists have proposed a mathematical model: WAM (Whack-a-mole) model for
expressing increment of mutation frequency depending on dose rates instead of total dose1, 2.
They are continuing to brush up the model now with biologists, radiation protection experts,
medical doctors etc. Here we would like to introduce the outline of this mathematical modeland to present the current tasks of this model and those verification results.

1. Whack-a-mole (WAM) model
It is well known that organisms have the potential to repair damaged biomolecules. Although
cells suffered damages are deleted or substituted by the various biological mechanisms, rarely
damaged cells remain as mutant cells. And also some of mutant cells disappear by mechanisms
to eliminate abnormal cells such as cell death. Therefore, it is quite important to consider thebalance between occurrence and disappearance of mutant cells in germ stem cells in order tounderstand the frequency of genetic influence on offspring.
We would like to propose the following formula representing the mutation frequency causedby radiation dependent on its dose rate1, 2. This model expresses increase and decrease of themutant frequency depending on the dose rate as binomial equation in addition to thefluctuation of mutant frequency by spontaneous mutation. We called this formula
Whack-A-mole (WAM) model to liken mutation to moles came out of the hole.
dF / dt = ( a0 + a1d ) – ( b0 + b1d ) F
F : mutation frequency
d : dose ratea0 : spontaneous mutation and those proliferation effect [/hour]a1 : mutation by the artificial radiation [/Gy]b0 : natural cell death effect [/hour]b1 : the effects of cell death by the artificial radiation [/Gy]
2. Comparison of WAM-theoretical values and experimental values in mouse
Russell WL. and his colleagues have been shown that the radiation dose rate effect on micemutagenesis. Their historical huge amount of experimental data indicated that apparentdifference in the mutation frequency between acute and chronic irradiation3.
We confirmed that ourtheoretical values calculated
from WAM model agree withthe actualFig.1
values of Russell’s
experimental results. Althoughalmost WAM theoretical values
were clearly well matched with
Russell’s results which are
categorized into two conditionsof acute exposure (72 or 90
R/min) and chronic exposure(0.0007 ~ 0.8 R/min), only thevalue of mutant frequency
estimated by WAM model at 0.8
R/min of exposure dose rate
apparently excess from its
experimental value (Fig.1). It
would be possible to summarize
in two reasons; 1) Depending on
the dose rate, the developmental stage of the irradiated sperm cells was different. 2) The timeinterval from the end of irradiation to the start of mating is not the same depending on
exposure conditions. Currently, we are reviewing their literature and papers4.

3. Search for ways to overcome barriers between research fields
We have been introducing the WAM model at domestic and international academic societies
etc., but unlike physicists, the reaction of biologists was often not so good. I am also a biologist,
so the reason can be roughly estimated. It seems to be due to the resistance to expressing thecomplex system of living organisms by one formula, and also to the weak consciousness
against mathematics itself. So, we are currently attempting to create animations that ourmodels can understand intuitively. Our challenge to overcome such barriers between
academic disciplines will continue.

References
1

Manabe Y. et al., Journal of the Physical Society of Japan 84, 044002 (2015)
Wada T. et al., Journal of Nuclear Science and Technology 53,1824-1830. (2016)
3
Russell WL. and Kelly EM., Proc. Natl. Acad. Sci. USA 80, 542-544. (1982)
4e.g. Russell LB., Mutation Research 753,69-90. (2013)
2

1A22
Production and isolation of At-211 for targeted alpha therapy at Osaka University
Atsushi Toyoshima1,2, Zijian Zhang1,3, Akimitsu Kanda3, Takumi Ikeda3, Soichiro Ichimura4,
Kazuhiro Ooe5, Yoshitaka Kasamatsu1,3, Takashi Yoshimura1,6, and Atsushi Shinohara1,3
1

Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University
2
3

Advanced Science Research Center, Japan Atomic Energy Agency

Department of Chemistry, Graduate School of Science, Osaka University
4

5

Department of Chemistry, Faculty of Science, Osaka University

Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of
Medicine
6

Radioisotope Research Center, Osaka University

Alpha-particle emitters are promising for the treatment of small tumors because the short recoil
range of α-particles emerged from radioisotopes conjugated to appropriate targeting agents issuitable for efficient eradication of cancerous cells with less harmful effects on surrounding healthyorgans. Among known α-emitting radionuclides, a limited number of those exhibits suitable nuclear
characteristics to the targeted alpha therapy (TAT). One of the potential candidates is astatine-211(211At) which has preferable properties of a moderate half-life of 7.2 hours and 100% α-decay
probability including that of its short-lived electron-capture (EC)-decay daughter 211gPo. At Osaka
University, we have recently started the collaborative project for the TAT using 211At. We have beendeveloping large-scale production of 211At, its chemical isolation, radiopharmaceuticals preparation,and clinical trials, all of which are mandated to establish the 211At-TAT. In this contribution, we
report the present status of the production of 211At at Research Center of Nuclear Physics (RCNP)
and its chemical isolation at Radioisotope Research Center (RRC).
Astatine-211 was produced in the 209Bi(α, 2n)211At reaction at RCNP. A metallic Bi targetof 10-30 mg/cm2 thickness was prepared on 10 µm-thick Al foil by vacuum evaporation. Typicalbeam current of 4He2+ ions was 0.5 particle µA. The Bi target was set at 45o to the beam axis in an
irradiation chamber. The 30-MeV α-beam delivered from the AVF cyclotron passed through a
HAVAR window, He cooling gas, 10 µm-thick Al cover foil, and then entered the Bi target with theincident energy of 28.2 MeV. Because the neighboring radioisotope 210At decays into a highly toxic
210

Po via an EC decay, the beam energy was adjusted to provide the incident energy on the target

lower than 28.6 MeV, which is the threshold energy of the 209Bi(α, 3n)210At reaction, to avoid
simultaneous synthesis of 210At. During the irradiation, the Bi target was cooled with a circulating
He-gas flow and circulating water. Irradiation time was 30 min to a few hours depending on requiredradioactivity of 211At.
After the irradiation, dry distillation was carried out at RRC to separate 211At from thetarget materials. We fabricated a simplified dry-distillation apparatus. In a typical procedure, mixed
helium and oxygen gas was used as carrier and reactive gas at a flow rate of 20 mL/min. We also
controlled a moisture content in the distillation system. The irradiated Bi target was placed in aquartz still and was heated up to 840oC using an electric tubular furnace. The exit of the quart
column was connected to a 4-way valve and then Teflon tube which was cooled with ice water totrap volatile astatine species. During accumulation of 211At on the trap, an X-ray of Po attributed to211

At was measured with a CdTeZn detector to monitor an trapped amount of 211At. After several

tens of minutes, trapped 211At was stripped with 100 µL of a desired eluent such as distilled water,
saline, or methanol, at a flow rate of 250 µL/min. The radioactivity of 211At was determined by γ-ray
spectrometry using a Ge detector. The 211At solution were supplied to pharmaceutical experiments,
animal examinations, or our chemical analysis experiments.
At present, after our optimization of the irradiation system, we can produce 211At at therate of 13 MBq/µA h using a thin Bi target. This means that production capability of our system is
23 MBq/µA h with a thick 40 mg/cm2 target, which is comparable to the IAEA-recommended valueof 25.3 MBq/µA h [1]. Chemical yield of 211At obtained with the 100 µL effluent in thedry-distillation was 80-90% under the optimum conditions. The separation time was typically 60 min.
In the workshop, results on our chemical analysis such as ICP-MS measurement on the sample willbe also presented.
Reference[1] S.M. Qaim et al. (Eds.), IAEA Technical Reports Series No. 473 (2011).

1A23
Radiolabeling of small molecules with astatine (211At) for theranostics
Yoshifumi Shirakami (Graduate School of Medicine, Osaka University)
Background:
Astatine (211At, T1/2=7.2hr) is an alpha particle emitter which is known as the promisingradionuclide for nuclear medicine therapy. Furthermore, 211At allows SPECT imaging since
the daughter nuclide of 211At, polonium (211Po, T1/2=5sec), emits X-rays (77 and 79 keV).
Thus, 211At and its labeled compounds are considered to be useful not only for therapeutics
but also for diagnostics (theranostics). No 211At labeled agents were launched yet in theworld at present. A clinical trial of 211At labeled BC8-B10 was initiated in the U.S. as theworld’s first clinical trial of211

At labeled agents in 2017 (Phase 1/2 for leukemia,

NCT03128034). While the chemical properties of astatine have not been well elucidated
since there are no stable isotopes of astatine, which make difficult or slow the developmentof 211At labeled agents. This article describes the chemistry of 211At aiming to develop
sodium astatide (211At) as a potential agent for thyroid cancer and also explains methods forradioastatination of small molecules.
Sodium astatide (Na211At):
Sodium astatide (Na211At) has been investigated for treatment of thyroid cancer as analternative to sodium iodide (Na131I) which is currently used in a clinical setting. It is wellknown that Na211At is accumulated in tumors expressing sodium iodide symporters (NIS) as
well as in normal thyroid in small animals. Several papers pointed out that the thyroid uptakeof Na211At is lower than that of Na131I (3 to 20 times, vary by paper) [1]. The reason of lower
accumulation of astatide in thyroid is not well understood. Astatide anion might not be able
to couple to thyroxine (a hormone of thyroid), unlike iodide anions, since the ionic radius ofastatide (2.3) is a little larger than that of iodide (2.16). Astatine-211 is produced by anuclear reaction of 209Bi(α,2n)211At. The produced 211At is separated and purified by a dry
distillation method or a wet solvent extraction method and obtained as an aqueous solution
in a cold trap. It is assumed that, in contrast to iodine, astatine prefer to present as higher
oxidation states, such as At[+1] and At[0], in addition to At[-1] in the aqueous solution. We
tried to prepare an aqueous solution of pure Na211At using reducing agents. Ascorbic acidwas one of the best agents for reducing the higher oxidation states of At-species into
astatide anions. The radiochemical yield of Na211At with 1% ascorbic acid was more than90%. The solution of Na211At with 1% ascorbic acid showed 3 to 5-times greater thyroid
uptake in rats and mice comparing with the solution without ascorbic acid. This result
demonstrated that the oxidation states of 211At affects pharmacokinetics of 211At labeled
compounds as well as chemical properties of them.

Astatination of small molecules:
Trialkylstannylated precursors can be used for preparation of astatinated molecules as well
as for preparation of iodinated molecules since the chemical properties of both astatine andiodine are alike [2]. The astatination reactions often require organic solvents andcomplicated procedures for heating, deprotection and purification. The residual precursors
including tin and by-products in the reaction mixtures should be eliminated from final drug
products. We attempted to develop a new method for astatination of phenylalanine (Phe) by
substitution

reactionofaborono-groupina

precursor

molecule(Fig.1).

Boronophenylalanine (BPA) or 2-fluoro-boronophenylalanine (FBPA) was reacted with
211

At-aqueos solution (1-10MBq) in the presence of N-bromosuccinimide as an oxidant atroom temperature for 30min. Radiochemical yields of 211At-(F)-Phe were more than 90%.
The products were stable in the aqueous solution at pH8.5 for 24hr. The borono-substitution
reaction is applicable for the astatination of the other arylboronates.

   Fig. 1 Astatination of phenylalanine analogue by substitution reaction of borono groupin precursor molecule

Future aspects:
Our goals of the studies are to prepare and supply 211At labeled agents for theranostics.
Both Na211At and 211At-(F)-Phe analogues will be the potential candidates. We need careful
about the designs of molecular structures and formulations of the drug products due tosome limitations of astatine from the chemical point of view as follows: 1) Astatine presents
as various oxidation states from +7 to -1 resulting in complicated properties for labeling, 2)
The energy of covalent bonding between astatine and carbon atoms are relatively weak. It is
crucial to ensure the stability of 211At labeled agents both in vitro and in vivo.
This work was supported by JSPS KAKENHI Grant number T16K102770.
References:[1] Larson RH, et al., Blocking [211

At] astatide accumulation in normal tissues: Preliminary

evaluation of seven potential compounds Nucl Med Biol 1998; 25:351-7.
[2] Meyer GJ, et al., Synthesis and analysis of 2[

211

At]-L-phenylalanine and 4-[

211

At]-L-

phenylalanine and their uptake in human glioma cell cultures in vitro Appl Radiat Isot 2010;
68: 1060-65.

1A24
Preparation of novel anticancer drugs using At-211

Kazuya Kabayama, Kazuko Kaneda-Nakajima, Yoshiyuki Manabe, Atsushi Shimoyama, Atsushi Toyoshima,
Atsushi Shinohara, Koichi Fukase
MS-CORE, Project Research Center, Graduate School of Science, Osaka University

The principal aim of this study was development of next-generation internal radiotherapy using
211

At conjugated with cancer targeting molecules.

First, we synthesized anti-CD20 antibody conjugated decaborane (B10H14) with polyethylene
glycol linker1-5).

211

At was produced by the cyclotron, and then quickly purified and combined

to decaborane conjugated antibody. Now we are getting this 211At combined antibody in about
80% yield.
Next, we performed cytotoxicity evaluation of 211At and this antibody using Raji cells (Blymphocyte cell line derived with Burkitt's Lymphoma). As a result, the time- andconcentration-dependent cell death were confirmed in both 211At and this antibody. In theimmediate future, we plan to examine that the same study with anti-HER2 antibody for breast
cancer, and in vivo study using some tumor-bearing animals.

1) D. S. Wilbur. et. al. Bioconjugate Chem., 2007, 18, 1226. 2) H. Nakamae. et. al. Cancer Res.,
2009, 69, 2408. 3) D. S. Wilbur. et. al. Nuclear Medicine and Biology, 2010, 37, 167. 4) D. S.
Wilbur. et. al. Bioconjugate Chem., 2011, 22, 1089. 5) D. S. Wilbur. et. al. Bioconjugate Chem.,
2012, 23, 409.

1A25
Imaging of the targeted alpha therapy for the clinical application
Tadashi Watabe, M.D., Ph.D., FANMB.
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate
School of Medicine
Targeted alpha therapy is receiving much attention in the field of theranostics becauseof its high biological effect to the target cancer cells. However, physiological uptakes in
non-targeted organs are also observed in the targeted alpha therapy as well as
beta-particle therapy, which might lead to the severe side effects. We should consider
about both maximizing the treatment effect in the tumor and minimizing the side effects
in the organs at risk. In the current clinical protocol of radium-223 for bone metastasisof the castration resistant prostate cancer, injected dose is decided by the body weight ofthe patient. To achieve dose optimization in the targeted alpha therapy, personalized
dosimetry is an ideal method by acquiring the whole body distribution in the firsttherapy as well as estimating the distribution of the target compound by pre-treatment
PET or SPECT. In astatine-211, whole body distribution can be visualized andquantitatively evaluated by gamma-camera imaging with targeting the x-ray which isemitted from the daughter nuclide (polonium-211). These imaging data can be used forthe dose optimization for the second targeted alpha therapy. In this talk, I would like tointroduce the recent achievements of our preclinical research using astatine-211 and theimportance of imaging in the targeted alpha therapy for the future clinical application.

2M01
Biomarkers and radiation therapy for patients with head and neck cancer
Jean-Philippe Foy (1,2), Cédric Chaveroux (1), Serge Manié (1), Nicolas Foray (1),
Pierre Verrelle (3,4), Pierre Saintigny (1,5)
1-Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard,
Centre de recherche en cancérologie de Lyon, Lyon, F-69008, France
2-Department of Oral and Maxillofacial Surgery, University of Pierre Marie Curie-Paris 6,
Pitié-Salpêtrière Hospital, Paris, F-75013, France
3-INSERM U 1196 , CNRS UMR 9187, Institut Curie, Orsay, F-91405, France
4-Université Clermont Auvergne, Centre Jean-Perrin, Clermont-Ferrand, F-63000, France
5-Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, F-69008, France
6-Department of Medical Oncology, Centre Léon Bérard, Lyon, 69008, France

Background: Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associatedwith a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive statusis recognized as a marker of increased radiosensitivity. We have recently proposed an approachfor the identification of molecular markers associated with benefit to radiotherapy in patients with
HPV-negative disease. Methods: Gene expression profiles from public repositories were
downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The
Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data
(GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set
Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and
GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366),
and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the
RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression,
biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset(659 pancancer cell lines, 140 drugs). Results: We identified 13 genes differentially expressed
between tumor and normal head and neck mucosa that were associated with radioresistance invitro and in patients. The 13-gene expression-based RadR score was associated with recurrencein patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It wassignificantly different among different molecular subtypes of HPV-negative HNSCC and wassignificantly lower in the "atypical" molecular subtype. An integrated analysis of RadR score withgenomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity
showed a significant association with CCND1 amplification, fibronectin expression, sevenhallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), andincreased sensitivity to elesclomol, an HSP90 inhibitor. Conclusion: Our study highlights theclinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation
strategies in HPV-negative disease. In our talk, we will summarize few other studies that haveproposed biomarkers of response or resistance to radiation therapy in head and neck cancer.

2M02
Present status of patient dose in large part of the world
Madan M. Rehani,
Massachusetts General Hospital, Harvard Medical School, Boston, USA(madan.rehani@gmail.com; mrehani@mgh.harvard,edu)
The issue of patient radiation dose has been receiving increasing attention globally.
Traditionally, when one talks about patient doses on a global scale, one is used to talking
about either a) collective effective dose to the population and United Nations ScientificCommittee on Effects of Atomic Radiation (UNCEAR) provides data on this or b) per
procedure patient dose in different imaging modalities and associated values of diagnostic
reference levels (DRLs). But for correlating patient dose with biological effects, one needs totalk about cumulative effective dose to individual patients. Unfortunately, this aspect has notreceived the attention that it should. In the past, tools to estimate cumulative dose were notavailable but currently many countries have the technology to track patient exposure history.
Besides technology, one needs to use patient identifier (ID) that is valid for life and is used in
medical records. Having a network of picture archiving and communication system (PACS)
that connects many hospitals in the region of the country or national network and using thesame patient ID has enabled tracking of patient doses. Additionally, several commercial
vendors are providing dose management systems that provide extensive information on
tracking of doses.
The key points in tracking of patient dose with relevance to biological effects are a)assessment of cumulative effective dose and cumulative organ doses to the individual patientand b) estimate of doses for assessing the potential for tissue reactions. Currently, there isdata available from imaging studies on thousands of patients who have received radiationdose in the range of 100 to 1100 mSv of effective dose or 100 to 3000 mGy to some of theimportant organs like breast, heart, lungs, bone marrow, eye, brain, esophagus or colon. We
have segregated patients in the category of malignant and non-malignant and in different age
groups: 0-30; 31-50 and over 50 years. Although the majority of the patients with higher
doses are in upper age groups of >50 and have malignant conditions, there are 1-5%
situations where patients are in lower age group (0-30 years) and also those who have nonmalignant disease. The data on the frequency of use of relatively high dose examinations, inparticular, computed tomography is reasonably available from many countries. The
overexposures and accidental exposures are not that common but cases of skin injuries inpatients undergoing continue to happen. Regulatory requirements in USA to bring all cases ofpatients undergoing fluoroscopic procedures with reference air kerma dose exceeding 2Gy
and 5Gy to the attention of Radiation Safety Committee of the institute have created data on
frequency of such cases. Data on temporal change in frequency and doses is scant but
scattered information is available from some studies that indicate positive trends in patient
doses. Currently, there is much more availability of patient dose information from developed
countries of the world primarily because of commercial availability of dose tracking systems.
The radiation exposure of patients provides a valuable opportunity for using patient
population for research on biological effects. Better availability of patient dose indicescurrently adds higher level of confidence in dose estimates and thus better correlation withradiation effects.

1

2M03
Millennial medical record project― Toward establishment of authentic Japanese version EHR and secondary use of medical data ―Hiroyuki Yoshihara, MD/PhD
Kyoto University, University of Miyazaki
The beginning of EHR can be traced back to the examination of the medical information common
standard in 1995 (MML: Medical Markup Language [1]). In 2001, EHR with database structure of
MML was developed and expanded to Miyazaki, Kumamoto, Tokyo, Kyoto (Dolphin Project)[2, 3, 4].
After that, the necessity of medical information management at national level and the importance of
secondary use of medical information came to be recognized. In 2015 the country level version of theDolphin Project "The Millennium Medical Record Project" began. We will increase the number ofconnected hospitals in 4 years until 2018 and prepare for secondary use of medical information
starting from 2019. We are aiming for independent profit including EHR department by revenue of
secondary use of data without relying on government subsidies.
In the first fiscal year (FY 2015), establish the foundation of the EHR center (database etc). At thesame time, we connected hospitals (11 facilities) already connected to the former EHR in Kyoto andMiyazaki to the center.
In fiscal 2016, the number of connected hospitals is increased, 23 hospitals are newly connected, andin fiscal 2017 more than 40 hospitals are scheduled to be connected and adjustment is continuing. In
FY 2018, which is the final year of the AMED research period, more than 40 hospitals, pharmacies,
etc. are planned to be connected (Fig. 1). The final goal is about 150 in the basic hospital class.

Figure 1. Concept of Millennial medical record. Make large-scale data
centers in Japan, accommodate data centers in each region, reduce costs,
and reduce operational burden rather than data center operation by region.

As shown in Figure 2, in the Millennium Medical Record Project, we will first build the EHR system inthe lower part of the figure (~ 2018) and precede the EHR service. With the enforcement of the
Next-Generation Medical Infrastructure Law, two newly established entities (Primary Use EHRManagement Organization, Secondary Use Certification Anonymous Processing Medical Information
Creation Business Operator) will be operated.

Figure 2 Outline of the Millennium Medical Record Project

References
1) Araki K, Ohashi K, Yamazaki S, Hirose Y, Yamashita Y, Yamamoto R, Minagawa K, Sakamoto N
and Yoshihara H: Medical markup language (MML) for XML-based hospital informationinterchange., Journal of Medical Systems; 24(3): 195-211, 2000
2) Akira Takada, Jinqiu Guo, Koji Tanaka, Junzo Sato, Muneou Suzuki, Takatoshi Suenaga, Ken
Kikuchi, Kenji Araki and Hiroyuki Yoshihara: Dolphin Project - Cooperative Regional Clinical
System Centered on Clinical Information Center, Journal of Medical Systems; 29(4): 391-400, 2005
3) JING-SONG LI, TIAN-SHU ZHOU, JIAN CHU, KENJI ARAKI and HIROYUKI YOSHIHARA: Design
and Development of an International Clinical Data Exchange System: The International Layer
Function of the Dolphin Project, Journal of the American Medical Informatics Association : 2011
4) Tadamasa Takemura, Kenji Araki, Kenji Arita, Toshiaki Suzuki, Kazuya Okamoto, Naoto Kume,
Tomohiro Kuroda, Akira Takada andHiroyuki Yoshihara: Development of Fundamental
Infrastructure for Nationwide EHR in Japan, Journal of Medical Systems: 2011

2A11
Potentials of Radiomics in Cancer Treatment
Hidetaka Arimura
Division of Medical Quantum Science, Department of Health Sciences
Faculty of Medical Sciences, Kyushu University

The radiomics is a novel field, which comprehensively analyzes a large number of medical
images, and extracts useful information that can make it possible to improve the decision
supports in the cancer treatment including surgery, radiation therapy, and chemotherapy. The
radiomics is a word derived from “radio”, which means radiological images (medical images ina broad sense), and omics. Omics consists of several study fields (genomics, transcriptomics,
proteomics, and metabolomics) that improve our understanding of tumor biology and clinicalmanagement of cancer by comprehensively analyzing genome, transcriptome, proteome, andmetabolome. The medical images, which are routinely and quickly acquired with low-cost in
clinical practices, represent the internal “phenotypic” information (e.g. anatomical,
physiological, and pathological information) on tumor regions and patients’ bodies. The
phenotypes result from the expression of an organism’s genetic codes, i.e., genotypes, as well as
the influence of environmental factors and the genotype-phenotype interactions. The genotypes
with mutations could determine cancer traits, which are involved in the prognoses of patients.
On the other hand, the genotypes are assumed to be encoded to the phenotypes expressed in the
medical images by biological processes, and then the radiomic features may be computed by“decoding” the phenotypes (medical images). “Decoding” medical images indicates theextraction of image features from medical images using computational image processing andanalysis techniques. Therefore, the radiomic features might be equivalent to the genotypes, andthus they could have associations with the cancer prognoses. In conclusion, radiomic features
could be considered to reflect cancer traits and prognoses.
Since the radiomic features could have potentials to be employed as “imaging biomarkers”
for decision-making in cancer treatment from the assumption mentioned above, the prognosesof patients or treatment outcomes could be predicted by using the features. The author will
explain the potentials of radiomics and its perspectives in cancer treatment.

2A12
Imaging database and radiomics
Akihiro Haga, Ph.D
Department of Medical Image Informatics, Graduate School of Biomedical
Sciences, Tokushima University
Radiomics can provide characteristics of entire tumors and of spatial and temporal
intratumoral heterogeneity with noninvasive and repeatable way [1]. Radiomics
converts medical imaging data into a high-dimensional feature space using a large
number of automatically extracted data characterization algorithms. A schematic
illustration of the representative processofextracting

radiomics

featuresisshown in Fig. 1. Extracted features may
be related with the outcome of tumor
phenotype, treatment response, anddifferentiate
tumors.

benignandRadiomics

havemalignant
drawn

an

interest due to their possibility of
uncovering tumor characteristics that
may

have

otherwise

failedtobeappreciated by the naked eye.
On the other hand, there are several
problems to be overcome in order toFig. 1: Representative process in radiomics. As well as
the shape and size based features (Global), texture based
features are extracted (GLCM, GLRLM, GLSZM, andNGTDM). For extraction of texture features,
pre-processing is necessary, which involved isotropic
resampling and gray-level quantization.

improve the radiomics prognosis of the outcome. One is that the radiomics
signature has been sensitive to the delineation of the volume of interest (VOI) [2],which is commonly subject to interobserver delineation variability. Second is avariation in medical images used in the radiomics analysis, that is, regarding image
quantification or normalization. Third is a limited accessibility to the medical
database. Above problems relate each other having inherent difficulties.
In this talk, I’ll show the application of radiomics for predicting the histology ofearly-stage non-small-cell lung cancer (NSCLC) by analysing CT images withinterobserver variability for tumor delineation in The University of Tokyo Hospital.
Radiomics features are extracted from four VOI delineated independently, andarea-under-the-curve (AUC) analysis is performed. It will be showed thatinter-observer variability in delineation is a significant factor in radiomics
performance.
One of the limitations of above study is the small cohort size, only 40 NSCLC
patients. For extended database, one needs to take carefully image quantification
into account. I’ll present other validation results by using the Cancer Imaging
Archive [TCIA, http://www.cancerimagingarchive.net/], which implies that thequantitative imaging technique is essential in further development of radiomics.
In quantitative CT imaging, the electron density estimation is the easiest way. On
the other hand, a diversity of medical imaging devices makes a novel image
reconstruction possible. In this talk, I also present the material decomposition
approach and functional imaging approach for an application in radiomics. In theseapproaches, an establishment of imaging database would be a crucial key, too.
[1] Aerts, H. J. et al. Decoding tumour phenotype by noninvasive imaging using aquantitative radiomics approach. Nat Commun 5, 4006 (2014).
[2] Haga, A. et al. Classification of early stage non-small cell lung cancers on
computed tomographic images into histological types using radiomic features:interobserver delineation variability analysis. Radiol Phys Technol. 2017,https://doi.org/10.1007/s12194-017-0433-2.

2A13
Radiomics on MRI field
Koji Sakai
Department of Radiology
Kyoto Prefectural University of Medicine
Literally “Radiomics” is a synthesized word that is derived from radiology and omics. The
meaning of omics is the science that systematically integrates wide information in one field. The
definition of radiomics reminds us “inter-disciplinarily work” and requires an interdisciplinary
collaboration.
In the real world, the main purpose of actual research of radiomics is to precisely explain therole of radiology such as, image diagnosis, decision making of therapy, treatment direction,
prognosis, follow-up, and to estimate the harmful effects of radiotherapy by effectively integrate1

the information obtained from radiological examinations (MRI, CT, PET, SPECT) .
The concept of radiomics is widely acceptable to medical field with the limited evidence of
application and many ongoing studies. Therefore, the relationships among the elements inradiomics are not well defined and have a potential to investigate new relationship to others.
It is possible that we can denote “Radiomics” as the advertisement board of theinter-disciplinarily work from the aspect of radiology. The progress of radiomics may clearly
define the position of radiology as “the center of collaboration”. Therefore, radiology can play therole of hub and strong function to further realize the meaning of inter-disciplinarily works.
Research on computer aided diagnosis (CAD) in information science and biomedical sciencehas been studied and made important role to establish basic techniques such as segmentation2and registration . As a prominent example, automated tumor extraction and size detection on
pulmonary CT has been continued.
The combination of CAD techniques with medical records, which include images, the analyzed
data of genes, proteins, and metabolites, and machine learning has created a new paradigm ofradiological research. The address of Radiological Society of North America (RSNA) President in2015 where the key word “Radiogenomics” took special attention as a trend of radiology field.
Consequently, some clinical applications of artificial intelligence (AI) came up to the gallery in
RSNA 2016.
I believe that the real face of “Radiomics” is a sign-board of radiology centered on integrating
multi-disciplinary collaboration and creation of new omics by radiology. It should be noted that
this is not only simple summation of each research field (mixing) but integration ofmulti-disciplinary field. Therefore, it is not “Radio-mix” but “Radiomics”.
The purpose of MRI radiomics on top five body parts were summarized as following figure (asof August 25, 2017).

Those were characterizing, grading of tumor, and investigating image feature, monitoring,
information for differential diagnosis, and correlation to histology. The top five MRI radiomics
3,4

5,6

7,8

studies were carried out on brain , breast , liver , prostate

9,10

11

, and rectal . On the top 5 bodyparts, the main target can be summarized as malignant tumor.
Through the review, many papers pointed out the problems of their study as follows: Small
cohortsize,

Retrospective

nature,Selection

bias,

Manuallesionsegmentationisoperator-dependent, and Very small lesions. Almost of all papers pointed out the “small cohortsize” was a big problem. It is easily understand that there is a limit to earn the cohort size at one
site.
In my talk, I will review some MRI based radiomics studies. I will also try to categorize thestudy design and show the stats of radiomics studies in the International Society in Magnetic
Resonance in Medicine (ISMRM2017) and its two official magazines, Journal of Magnetic
Resonance Image and Magnetic Resonance in Medicine. In addition, I will try to describe thecurrent status of MRI based radiomics.
Reference
1.
2.
3.

Gillies RJ, Kinahan PE, Hricak H. Images are more than pictures, they are data. Radiology 2016: 278: 563-77.
Castellino RA. Computer aided detection (CAD): an overview. Cancer Imaging 2005; 5(1): 17-19.
Zhou M, Chaudhury B, Hall LO, et al. Identifying spatial imaging biomarkers of glioblastoma multiform for survivalgroup prediction. J Magn Reson Imaging 2017; 46: 115-23.
4. Adduru VR, Michael AM, Helguera M, et al. Leveraging clinical imaging archives for radiomics: reliability of
automated methods for brain volume measurement. Radiology 2017; 284: 862-9.
5. Li H, Zhu Y, Burnside ES, et al. MR imaging radiomics signatures for predicting the risk of breast cancer recurrence
as given by research versions of MammaPrint, Oncotype DX, and PAM50 Gene Assaysg Radiology 2016; 281:
382-91.
6. Bickelhaupt S, Paech D, Kickingereder P, et al. Prediction of malignancy by a radiomic signature from contrast
agent-free fiffusion MRI in suspicious breast lesions found on screening mammography. J Magn Reson Imaging
2017; 46: 604-16.
7. Zhou W, Zhang L, Wang K, et al. Malignancy characterization of hepatocellular carcinomas based on texture
analysis of contrast-enhanced MR images. J Magn Reson Imaging 2017; 45: 1476-84.
8. Chen X, Ma Z, Huang Y, et al. Multiparametric MR diffusion-weighted imaging for monitoring the ultraearly treatment
effect of Sorafenib in human hepatocellular carcinoma xenografts, J Magn Reson Imaging 2017; 46: 248-56.
9. Ginsburg SB, Algohary A, Pahwa S. Radiomic features for prostate cancer detection on MRI differ between thetransition and peripheral zones: preliminary findings from a multi-institutional study, J Magn Reson Imaging 2017;46: 184-93.
10. Lin Y, Lin G, Hong J. Diffusion Radiomics Analysis of intratumoral heterogeneity in a murine prostate cancer model
following radiotherapy: pixelwise correlation with histology. J Magn Reson Imaging 2017; 46: 483-9.
11. Liu L, Liu Y, Xu L, et al. Application of texture analysis based on apparent diffusion coefficient maps in discriminating
different stages of rectal cancer. J Magn Reson Imaging 2017; 45: 1798-808.

2A21
Contribution of a biological analysis platform to support the medical
management of radiation accident victims
Ulrike Kulka, BfS
An indispensable element of managing a radiation emergency is reconstruction of thepersonal, absorbed dose. This will not only help in selecting the optimal treatment, but will
also provide the emergency victim with confidence that he/she is properly diagnosed. The
latter factor is particularly important following large-scale radiation emergencies, where
many people will not know whether they have been exposed or not (the so called worriedwell). In such cases, retrospective personal dosimetry can provide immense help and to thisend a European Network of biological and retrospective physical dosimetry was established,comprising 26 organisations from 16 European countries. Among them are researchorganisations, universities, hospitals, regulators and radiation protection authorities.
Together they provide competences in various fields for emergency preparedness, forradiation research and for radiation protection of patients and personnel. This configuration
assures access to laboratories with expert knowledge in different biological assays andphysical techniques for individualised dose assessment.
The initial point of the network was to focus on emergency preparedness and response inlarge-scale radiological incidents by enabling individualised retrospective dose assessment
for possibly exposed people, first responders, but also for distressed “worried well”
individuals. In such situation, the concerted action of the network partners can help torebuild trust and prevent a confidence crisis in the affected population groups. Beyond that,the knowledge of the actual received dose is of high importance for the optimal medical careof the actually exposed people. However it has turned out that the network can also
contribute to radiation protection in general, including the application of ionising radiation inradiation therapy and nuclear medicine units in hospitals. This will be done by providing ananalysis platform to enable individualized approaches, also for smaller or remote hospitals,
enabling individualised approaches in medical treatment of patients, e.g. by taking into
consideration the individual radiation sensitivity.
Thus, the network with its ready-to-use operational basis, quality assurance and education &training plans, is of benefit for emergency preparedness and response as well as foroccupational and medical radiation protection. Even though RENEB is a European network,
successful collaborations have been initiated with colleagues from all over the world andlinks to global institutions as WHO and IAEA have been established.
Most of the network partners are also involved in radiation research and are members of theEuropean radiation protection platforms MELODI, EURAMED, EURADOS, NERIS and
ALLIANCE. Now, as a legal association the network is complementary to these existing
platforms.

2A22-F E E E
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2A23
Medical Radiation Protection Research Strategies in Europe
And the role of the Medical Physicist in Europe
Christoph Hoeschen
Otto-von-Guericke University Magdeburg, Faculty of Electrical Engineering and Information
Technology, Institute of Medical Technology, Universitätsplatz 2, 39106 Magdeburg,
Germany
Over the last decades, there has been a strong movement within Europe to build up strategic
research agendas and set up platforms of interested people to foster this approach for the strategicplanning of research in Europe. This has been applied to radiation protection research especiallysuccessful with the set-up of MELODI (Multidisciplinary European Low Dose Initiative), EURADOS(The European Radiation Dosimetry Group), ALLIANCE (European Radioecology Alliance) and NERIS(European Platform on preparedness for nuclear and radiological emergency response and recovery)
and their corresponding SRAs. For many years, a medical approach was missing in terms of research
regarding radiation protection for medical applications of ionizing radiation. Therefore, MELODI and
EURADOS set up a memorandum of understanding with the medical associations using ionizing
radiation in Europe: European Association of Nuclear Medicine (EANM), European Federation ofOrganisations for Medical Physics (EFOMP), European Federation of Radiographer Societies (EFRS),
European Society for Radiotherapy and Oncology (ESTRO) and European Society of Radiology (ESR).
In addition within the OPERRA project a task was funded to revive the medical radiation protection
field. This task together with the memorandum of understanding was used by the five associations
mentioned above to set up a first strategic research agenda. In the talk this strategic research agenda,
which can be found on the internet or as a peer-reviewed paper in Insights into imaging in 2017, will
be presented and explained. The structure is built along the lines of the main aspects of radiation
protection in medical application of ionizing radiation. It puts a strong emphasis on the necessity of aclear transfer strategy of the research results into clinical practice and to harmonise practicethroughout Europe. This will be explained in the talk as well as some major aspects of the content of
the strategic research agenda.
During the exercise of building such a strategic research agenda it became very clear that it isnecessary toa) Keep this document a living document and refresh it regularlyb) Further actions are needed to explain, promote and lobby for the content of the documentc) Build up structures to identify and foster groups for answering call or identified researchneeds.
Therefore, the five medical associations (EANM; EFOMP; EFRS; ESTRO; ESR) decided to set-up aplatform for medical radiation protection research. This platform is called EURAMED (The European
Alliance for Medical Radiation Protection Research) and it was raised as a Joint Initiative from EIBIR.
In October 2017 it became a legal entity and we are now open for membership applications. Due tothe process of setting-up a dedicated strategic research agenda for medical radiation protection it
became more evident that this task is of great importance and that there are strongly related aspects
with low-dose radiation research. Therefore in 2017 it was already possible to start with a large
European commission funded project called MEDIRAD, which is combining medical radiation
protection aspects with radiation biology, radiation epidemiology and other aspects of (low-dose)radiation protection research. This is a very convincing example on how it was possible with this
EURAMED effort together with the other platforms to foster medical radiation protection research inEurope. In addition, EURAMED was invited by the other platforms to take part in their common
activities for example within the CONCERT EJP project.
Within the above mentioned strategic research agenda for many aspects reference is made to theEuropean directive 2013/59, which is called pretty often, basic safety standard. This document
decided upon within the European commission and parliament in 2013 is replacing three former
separate directives which had been dealing with ionizing radiation and the protection against it.
Within this basic safety standard there is a number of new functions / persons defined in radiation
protection and especially also in medical radiation protection. One of these functions is the medical
physics experts (MPE). In the talk the requested tasks as well as the requirements to the education
for such a medical physics expert will be explained. There will also be a number of examples how thisis or will be handled in the different member states. The historical context about the objectives of
medical physicists in the past will be given and how this will be extended for what reasons. The
directive 2013/59 has to be put in place by legal actions of each country in 2018.
The very interesting aspects is that this legal requirement fit very well with the requirements formeaningful research in the field of medical radiation protection as defined by the strategic research
agenda or other documents provided in the meantime like strategic research statements, common
roadmap between the platforms etc. It will also hopefully foster the development of the strategic
research agenda further to implement new aspects like for example artificial intelligence or others
into the tasks. It can be foreseen, that a very solid ground has been laid for novel and meaningfulresearch in medical radiation protection and its implementation into clinical practice for the benefitof the patient using expertise of all participating professions including medical doctors and to a large
extend medical physicists. It is our obligation to make the best out of this chance and we would be
happy to share our experience with all those interested outside Europe.

3M01
BER2018 Presentation Abstract
Dr Jacques Repussard (France), MELODI Past president
Title: Understanding low dose radiation exposure effects : MELODI’s views on developing
international cooperation
Abstract:
In the aftermath of the Chornobyl nuclear accident which affected directly most European countries
to various degrees, and also in the context of fast growing medical use of radiation for imaging andtherapy purposes, the health risks associated to low dose radiation exposure have become an issueof societal concern. Unfortunately this concern is compounded by the fact that science is so far
unable to provide satisfactory answers about health risks related to such exposure, due to significant
remaining uncertainties, both in the understanding of underlying biological phenomena associated tosuch exposure, and in the data resulting from epidemiological studies.
In this context MELODI was set up a decade ago, in order to facilitate the steering of researchstrategies and thus focus efforts on priorities aiming at reducing such uncertainties. This needed a
special cooperation between research policy makers at European and national levels on one hand,
and the competent communities in the scientific disciplines concerned by low dose effects researchon the other hand, which was illustrated by the publication by the European Commission, in 2009, of
the “Report on European low dose risk research” of the “High Level and Expert Group” (HLEG).
MELODI’s key operations lead to the development and annual updating of a Strategic Research
Agenda (SRA) and derived initiatives concerning education and training and scientific research
infrastructures. These documents serve as a basis for the definition of research and training calls
which are published periodically by EURATOM, or broad ranging EURATOM funded projects such as
OPERRA, or more recently CONCERT, a project also co-funded by several EU member states.
The maturation of such strategies is slow, and a first positive result has been the widespread
understanding that the answers to the questions raised in the MELODI SRA could not be discovered
without intense and long range focused multidisciplinary cooperation, bringing together biology,
medicine and molecular epidemiology, a mode of work which is gradually recognized as the best way
forward.
Of course, there is no reason why such a scientific cooperation model should be restricted to theEuropean research community. Indeed, considering the complexity of the biological phenomena to
be investigated in order to fully explain the many effects (harmful or not) of human low dose ionizing
radiation exposure, there is a strong argument to promote the development of such multidisciplinary
approach in a multilateral context associating countries which have so far provided major scientificresults contributing to the understanding of low dose radiation effects, such as Japan and the USA.
However, an effective move in that direction will require the development of an appropriate
multilateral framework going beyond the traditional bilateral arrangements, with the active supportof research policy makers at governmental level, and of the leadership of the scientific communities
in the disciplines concerned. Such an initiative would most certainly be welcome by internationalorganizations such as NEA, IAEA, WHO and ICRP.

3M02
Electric Power Research Institute International Dose Effect Alliance
Donald A. Cool, Ph.D.
Technical Executive
Electric Power Research Institute1300 West WT Harris Blvd, Charlotte, NC, 28252 USA
The Electric Power Research Institute (EPRI) is a non-profit research organization dedicated to the publicbenefit and the advancement in electrical power. EPRI is structured with a number of sectors, with
nuclear generation being one such sector. EPRI interest in low dose and dose rate ionizing radiation
effects dates back almost 10 years, with the initiation of activities to support the need to better
understand the relationships between radiation dose, and health impact implications. In 2015, EPRI
identified the need for a forum to exchange information on research programs and results on a global
scale and initiated the International Dose Effect Alliance (IDEA). The vision of IDEA is for an international
platform for information exchange, discussion, cooperation, and collaboration in low dose radiation
research. The first workshop was held in November 2016, and a second workshop was held in
December 2017. Amongst other outcomes from the December 2017 workshop, a facilitated discussionof participants identified priorities for research, including: communications; individual sensitivity andsusceptibility; data capture and model creation; integration of epidemiology and biology; mechanisms ofcancer and biomarkers; and non-cancer effects. Looking forward, EPRI plans to continue cooperation
with international organizations and groups on alignment of strategic research agendas, andcollaborations to begin development of models that can bridge the gap between radiation biology
studies and results of epidemiological cohorts.

Abstract for the International Workshop on the Biological Effects of Radiation- Bridging the gap between radiobiology and medical use of ionizing radiation –3M03

Low-Dose Radiobiology Program at Canadian Nuclear Laboratories: Past, Present and Future
Dmitry Klokov, Yi Wang
Canadian Nuclear Laboratories, Chalk River, Ontario, Canada

In recent years, it has been increasingly acknowledged that achieving climate change goals set forth at
the Paris Conference of Parties to the United Nations Framework Convention on Climate Change may
not be possible without nuclear power generation. However, world-wide acceptance of nuclear power
as a major contributor to climate change control is dependent on a robust and reliable system ofradioprotection. Such system needs to be scientifically justified. Yet, the current international system ofradioprotection that is based on the Linear-No-Threshold (LNT) hypothesis falls short of suchrequirement. Large body of scientific evidence shows that biological responses of cells and organisms to
low doses of ionizing radiation (LDR) are not linear. As a result, continuous and heated debates about
the ability of the LNT model to predict human health risks associated with exposure to LDR occur among
various communities, including the scientific community. To rectify this controversy, there is a need forlarge-scale international collaborative groups and consortia aimed at carrying out relevant biologicalstudies using a combination of experimental approaches. The single most important feature of suchstudies appears to be the broad coverage of biological responses to LDR exposure – from early DNA
damage and DNA damage signalling events to long-term health outcomes, such as cancer, all studied
and considered within a single context. The resulting deep scientific understanding of the effects of LDR
can be used to improve the radioprotection system.
To address this need, a comprehensive low-dose Radiobiology research program has been established at
Canadian Nuclear Laboratories (CNL), formerly known as Atomic Energy of Canada Limited. CNL is afederally and privately funded Science and Technology organization that undertakes research anddevelopment (R&D) activities in various areas of Nuclear Sciences, including Radiobiology. CNL has astrong and reach legacy in Radiobiology, in particular low-dose Radiobiology. The Biological Research
Facility build at CRL in 1990s is equipped with a low-dose animal irradiation hall called the Gamma Beam.
It is located within the boundaries of a specific pathogen free animal facility such that chronic low-dose
irradiation experiments can be performed continuously during the entire animal life span. This globallyunique facility has been home to various large scale low-dose mouse in vivo studies that madesubstantial contribution to the filed. Thus, studies lead by Dr. Mitchel at CNL and showing that LDR
delays the onset of endogenous tumorigenesis in mice in vivo (1, 2) has been cited more than 100 times
each, providing a foundation for subsequent mechanistic mouse studies. These reports were precededby earlier highly cited in vitro studies demonstrating radioadaptive responses in mammalian cells (3, 4).
In late 2000s, low-dose Radiobiology program at CNL was expanded and enhanced to include molecularbiology, immunology, epigenetics and other approaches, which allowed studying biological effects of
LDR at broader and deeper levels. This was accompanied by partnering up and leveraging the CNL
program with international organizations and consortia, such as European Union (EU) funded NOTE
program (Non-Targeted Effects) and the French Institute of Radiological Protection and Safety (IRSN).
Beside the mandate from the Government of Canada, various other national and international stakeholders, such as Health Canada, Canadian Nuclear Safety Commission and CANDU Owners Group,
expressed strong support in the low-dose Radiobiology program at CNL. As a result, world-wideAbstract for the International Workshop on the Biological Effects of Radiation- Bridging the gap between radiobiology and medical use of ionizing radiation –recognition of the CNL Radiobiology program continues to grow evident from recent scientificpublications and the involvement of CNL scientists at international forums and programs as invited
speakers and/or experts in low-dose Radiobiology.
Recent studies carried out at CNL showed that spleen lymphocytes from mice exposed to low-dose
gamma-radiation exhibited higher DNA repair capacity via nucleotide and base excision repair pathways.
Interestingly, DNA double-strand break repair was not affected. Consistent with this, LDR-exposed cells
in vitro had a delayed onset of senescence or cellular aging. This was accompanied by a substantialchanges in miRNA expression profiles, suggesting a strong role of epigenetic mechanisms in LDR effects.
These results were partially confirmed in the in vivo mouse model of aging using markers or aging
assessed in the kidneys of aged control or aged LDR-exposed mice. Additionally, we demonstrated thatLDR exhibited overall stimulatory effect on the immune system of mice in vivo. Cancer, being an aging
related disease, has a strong mechanistic overlap with aging (5), with the immune system playing crucialrole in tumorigenesis (6). Our results therefore provide a link between early DNA damage and repair
responses and late systemic outcomes, such as modulation of the immune system and aging, allconverging on and affecting tumorigenesis. Furthermore, our most recent results showed that LDR
exposure of muscle stem cells partially restored their aging-related decline in function (muscle fibre
formation). Our current studies are aimed at obtaining even deeper insight into mechanisms underlying
responses to LDR and affecting systemic health risks - through all levels of biological organization, frommolecules to tissues.
With closure of the low-dose radiation research program funded by the U.S. Department of Energy inlate 2000s, the CNL low-dose Radiobiology program remains one of the world largest efforts in the field.
Unlike former and current EU low-dose research programs (DoReMi, MELODI, CONCERT) that provide
support to dozens of independent laboratories and whose research priorities may not necessarily lie
within low-dose Radiobiology, the CNL based program is specifically dedicated to and focused on thisarea. Being centrally coordinated and overseen, supported by unique facilities and a skilled professionals,
the CNL low-dose Radiobiology may be viewed as a centre of excellence in low-dose radiation research.
Nonetheless, our team strives to build further links with laboratories, organizations and programs worldwide that are strongly dedicated to understanding the biology of LDR effects.
References
1.
2.
3.
4.
5.
6.

R. E. Mitchel, J. S. Jackson, R. A. McCann, D. R. Boreham, Radiat Res 152, 273 (Sep, 1999).
R. E. Mitchel, J. S. Jackson, D. P. Morrison, S. M. Carlisle, Radiat Res 159, 320 (Mar, 2003).
E. I. Azzam, S. M. de Toledo, G. P. Raaphorst, R. E. Mitchel, Radiat Res 146, 369 (Oct, 1996).
E. I. Azzam, G. P. Raaphorst, R. E. Mitchel, Radiat Res 138, S28 (Apr, 1994).
J. P. de Magalhães, Nature Reviews Cancer 13, 357 (2013).
S. Palmer, L. Albergante, C. C. Blackburn, T. J. Newman, Proceedings of the National Academy of
Sciences, (2018).

3M04
Planning and Acting Network for Low Dose Radiation Research (PLANET) and promotion for
integrated network in Japan

Yutaka Yamada, Tetsuo Nakajima, Michiya Sasaki, Imaoka Tatsuhiko, Daisuke Iizuka, Shizuko
Kakinuma and Yoshiya Shimada,National Institute of Radiological Sciences, National Institutes for Quantum and Radiological
Sciences and Technology
Anagawa 4-9-1, Inage-ku, Chiba 263-8555, JAPAN

There are important issues for low dose exposure, especially decreasing uncertainty of risk
estimation of low dose/low dose-rate exposures. Desirable approach is to establish mechanistic
and numerical model based on stem cell biology and radiation biology at high dose rate, andthen to underpin the selection of appropriate risk model of chronic exposures.
In order to carry out these researches steadily and continuously, it is necessary to promotecollaboration among stakeholders in and outside Japan. Therefore, we decided to establish
all-Japan network among regulators, academia and research institutes, and other stakeholders(incl. industries). The tentative name of the network is PLANET; Planning and Acting Network
for Low Dose Radiation Research.
National Institute of Radiological Sciences (NIRS) set up preparatory committee for PLANET
in 2016 and appointed 9 specialists for radiation protection, radiation biology, epidemiology,
and dose assessment, and summarized the results on the report (1). The preparatory committee
discussed issues for research to improve risk estimation and identified 5 priorities the issues andneeds, as follows; 1) Epidemiological studies of the low dose/low dose rate radiation designed
for a risk evaluation appropriately, 2) Studies of the mechanism elucidation for risk evaluationsof the low dose/low dose rate radiation, 3) Integrate studies to use animal experiment data for
the interpretation in the epidemiological studies, 4) Studies to elucidate the association between
age, sex, heredity factor, lifestyle and radiation, 5) Database compilation including negative
data and saving archives of experiment samples.
The preparatory committee also discussed a collaborative system of PLANET involving all
sectors in Japan, including authorities, academia, universities and research institutes of radiation
research, and proposed support system for cooperation and collaboration researches among
related researchers and institutes. This cross-sectoral network should also aim to work together
with international organizations and cooperation both in Japan and abroad.

Nuclear Regulation Authority (NRA) entrusted NIRS with a strategic promotion for theradiation safety and protection research from 2017. This promotion is intended to supports the
setup of the networks for problem solution to radiation protection and build an umbrella typeplatform which integrates the networks. In addition, the promotion extracts the priority theme of
the radiation safety and protection research.
During the first year of this promotion, NIRS asks Japan Health Physics Society, JapaneseSociety of Radiation Safety Management, the Japanese Radiation Research Society, Japanese
Association for Radiation Accident/Disaster Medicine and PLANET for the suggestion of thepriority theme of the future radiation safety and protection research. The theme of the research
is divided into 6 general categories; 1) Biological effect and risk, including low dose/low dose
rate radiation effect, 2) Safety use of the radiation, 3) Measures taken against nuclear andradiation accident, 4) Environmental radiation and radioactive waste, 5) radiation measurement
and estimation, 6) Radiation education and risk communication.
A meeting to report the results is held to perform an argument for the consensus building in theumbrella type platform about the priority theme of the research. Finally, NIRS submits thereport about the priority theme to NRA, and NRA decides the theme of the next promotion inreference to the report.

PLANET is a network for low dose/low dose rate radiation research including basic science.
Multidisciplinary experts of PLANET contribute to a basic and regulatory science about low
dose/low dose rate radiation risk evaluation.

Acknowledgements: Thanks to Dr. Kazuo Yoshida and Dr. Toshiyasu Iwasaki, Central
Research Institute of Electric Power Industry, who contributed PLANET(1) Report of the preparatory committee for PLANET (Japanese);
http://www.nirs.qst.go.jp/publication/radiation_risk/01.pdf

3M05
JSPS committee “multidisciplinary research on the biologicaleffects of radiation”
Takahiro Wada
Department of Pure and Applied Physics, Kansai University, Suita, 564-8680 Osaka, Japan
In order to promote the research in low dose and low dose-rate radiation, as well as inmedical radiation, we established a committee “Multi-disciplinary research on the biological effectsof radiation” in JSPS (Japan Society of Promotion of Science). The aim of the committee is topromote the inter-disciplinary discussions on the biological effects of radiation and to enhance
multidisciplinary researches in these fields so as to integrate individual knowledges in various
fields.
After the accident at Fukushima Daiichi Nuclear Power Plant in March 2011, it became
immediately clear that the accurate, science-based information regarding risks of radiation
exposure was scarce. A serious divergence in views has emerged between physics and biology,
medical providers and researchers. Researchers in various fields such as epidemiology, animal
experiments, cell research, and molecular biology have been making much progress with theirstudies on health effects of ionizing radiation. More than a century of radiation research hasprovided us with extensive information on health effects and biological mechanism caused byradiation exposure, especially for moderate to high dose radiation. This has contributed especiallyin determining the standard criteria of radiation protection. However, there has not been aconsensus on the biological effects of low dose radiation and, in particular, low dose-rate radiation
mainly due to the lack of inter-disciplinary communication. Multidisciplinary collaboration is truly
needed to solve the long-standing problems in biological effects of radiation.
As one of the main topics of this committee, we promote inter-disciplinary discussions
between radiobiologists and medical researchers. Rapid increase in radiological procedures
during the past century has made significant contribution to the human health. Nowadays, medical
radiation has become a major source of human exposure to ionizing radiation. Such widespreaduse of ionizing radiation in medical practice alerts the medical community to carefully optimize theprocedures considering the benefit and risk of each patient. However, the health effects have notbeen confirmed for low dose and low dose-rate of radiation exposure. As medical use of radiation
is expected to expand globally, the scientific research to clarify the biological effects of low-doseand low-dose-rate exposure is essential not only for optimization of the current procedures but
also for future development of new technology. We believe the integrative efforts ofmultidisciplinary fields will solve the problem. We hope that this international workshop will ignite
such activities.

3A11
Radiation protection in therapy with radiopharmaceuticals
Makoto Hosono, MD, PhD
Kindai University Faculty of Medicine, Osaka, Japan

Introduction
Radiation protection in medicine covers in principle, medical exposure, occupational exposure, and public
exposure in association with various clinical circumstances. Medical exposure involves not only patients but also
their comforters and carers, and volunteers in biomedical research. Medical exposure of patients has unique featuresthat affect how the fundamental principles are applied [1]. Application of dose limits, which is one of the fundamental
principles of radiation protection elsewhere, is not undertaken in medical exposure. This is because such dose limits
would often do more harm than good in the course of treating patients. Two fundamental principles of generalradiation protection, justification and optimization, apply in medicine in a different way. Justification in radiation
protection of patients is unique in that the very same subject enjoys the benefits and suffers the risks associated with aradiological procedure. Optimization of protection for patients is also unique in that radiation therapy gives
intentional radiation for the purpose of treatment, and diagnostic procedures give the benefit and the risk to the same
subjects. Therapy with radiopharmaceuticals, namely radionuclide therapy (RNT), requires deliberate radiation
protection standards because it uses unsealed radionuclides and gives therapeutic radiation doses in humans.

From Radionuclide Therapy to Theranostics
The use of radiopharmaceuticals for therapy using novel radionuclides, including alpha emitters, compounds andprobes, has been increasing for the treatment of various tumors, that is, RNT, in connection with which “theranostics”
has been established. Theranostics means a method of combining diagnosis and therapy and enhancing the efficacy
and safety of procedures to an individual patient. In nuclear medicine, theranostics usually refers to a combination ofimaging and RNT in oncological nuclear medicine [2]. Conventional imaging and treatment of iodine-131 therapy for
differentiated thyroid cancer, and Zevalin therapy with indium-111 antibody and yttrium-90 antibody to B-cell
non-Hodgkin's lymphoma can be examples of theranostics.

Dosimetry-guided Personalized Therapy
As theranostic procedures currently attracting attention in nuclear medicine, somatostatin receptor imaging forneuroendocrine tumors and PRRT (peptide receptor radionuclide therapy) have attracted attention, and a large-scaleclinical trial of Lutetium-177 Dotatate against neuroendocrine tumors has been conducted [3]. Also, imaging with
Ga-68 labeled ligands targeted to PSMA (prostate specific membrane antigen) expressed in prostate cancer and RNTwith Lu-177 labeled ligand are currently being conducted mainly in Europe. In addition, alpha-emitter Ac (actinium)

-225-labeled PSMA ligand has been reported to have a dramatic therapeutic effect on advanced prostate cancer [4]. In
these procedures, dosimetry based on imaging is critical in guiding subsequent therapies. The European directive on
basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning forradiation therapies including radiopharmaceutical therapies. The directive comes into operation February 2018.
Dosimetry-guided practices will have significant implications for the evolution of RNT (Figure 1).

Conclusions

RNT combined with imaging and dosimetry is undergoing a significant expansion, and such dosimetry-based
treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of thetreatments [5].

Figure 1. Radionuclide Therapy guided by Imaging and DosimetryRadiopharmaceuticals:
Photon-emittersRadiopharmaceuticals:
Beta- or alpha-emitters

Photons emitted from RNT

Imaging

Radionuclide
therapy

Imaging

Confirm tumor accumulation
Staging
Dosimetry

Radiation to targets

Confirm tumor accumulation
Tumor response
Dosimetry

References
1.

ICRP Publication 105. Radiation protection in medicine. Ann ICRP, 2007. 37(6): p. 1-63.

2.

Moek, K.L., et al., Theranostics Using Antibodies and Antibody-Related Therapeutics. J Nucl Med, 2017.
58(Suppl 2): p. 83S-90S.

3.

Strosberg, J., et al., Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med,2017. 376(2): p. 125-135.

4.

Kratochwil, C., et al., Targeted Alpha Therapy of mCRPC with (225)Actinium-PSMA-617: Swimmer-Plotanalysis suggests efficacy regarding duration of tumor-control. J Nucl Med, 2018.

5.

Stokke, C., et al., Dosimetry-based treatment planning for molecular radiotherapy: a summary of the 2017
report from the Internal Dosimetry Task Force. EJNMMI Phys, 2017. 4(1): p. 27.

3A12
Experimental evaluation of the carcinogenic effect of carbon ions and neutrons in children
Tatsuhiko Imaoka, Mayumi Nishimura, Kazuhiro Daino, Masaru Takabatake, Hitomi Moriyama,
Yukiko Nishimura, Takamitsu Morioka, Yoshiya Shimada, Shizuko Kakinuma
National Institute of Radiological Sciences (NIRS),
National Institutes for Quantum and Radiological Science and Technology, JapanIon beam radiotherapy is a form of cancer therapy which uses accelerated ions such as carbon
ions and protons. As compared with protons, the use of carbon ions is considered to improvetreatment by permitting more accurate dose localization and stronger cell killing attributed to the
sharp Bragg peak and high linear energy transfer (LET). NIRS has been one of the leading
institutions of carbon ion radiotherapy in the world.

Radiation types relevant to ion beam radiotherapy
Because Bragg peaks of ion beams are normally too narrow for therapeutic applications,spread-out Bragg peaks (SOBP) have been devised to obtain a broad and uniform dose distribution.
In carbon ion radiotherapy, fractionated irradiation with a beam with 6-cm SOBP, which isdeveloped from the 290-MeV/u carbon ions and has an LET range of 40 90 keV/‫ﺼ‬m within the
SOBP component, has been used to treat several cancer types. Normal tissues can be exposed to 1)
the plateau region of the carbon ion beam, which has a lower LET of 14 keV/‫ﺼ‬m, and 2) fastneutrons, which are generated at the collimators and in the patient body, having a broad energy
spectrum covering the most biologically potent band of 0.1 2 MeV. Dose evaluation studies haveindicated lower neutron dose in carbon ion radiotherapy than proton radiotherapy.

Second cancer risk from ion beam radiotherapy
Although such advances in therapy have contributed to longer survival times of patients, latesequelae of therapeutic treatments are in turn becoming the next concern. Among the most serious ofsuch sequelae are second cancer, for which conventional forms of radiotherapy are an establishedrisk factor. Young cancer patients are especially affected by this issue, as they are expected to live a
longer life than older patients. Advance in ion beam radiotherapy led ICRP to publish arecommendation on relevant radiological protection (Yonekura et al. 2014), although the issue of
second cancer was not much discussed because of the scarcity of evidence. Major scarcity lies in theinformation on the carcinogenic effect of relevant radiation species, as compared to low LET
radiation (such as ‫ ﺳ‬rays), required in predicting second cancer risk.

Animal experiments to measure risk of carcinogenesis
Breast cancer is a common second cancer accompanying conventional radiotherapies ofchildhood and adult cancers. We used the rat mammary carcinogenesis model to study the effects of‫ ﺳ‬rays (137Cs), carbon ions (290 MeV, 14 keV/‫ﺼ‬m) and fast neutrons (2 MeV) irradiated at different
ages on subsequent development of breast cancer (Imaoka et al. 2013, 2017). Female rats at 1, 3 and7 weeks of age (neonatal, prepubertal and postpubertal, respectively) were whole-body irradiatedwith ‫ ﺳ‬rays (0.2 2.0 Gy), carbon ions (0.2 2.0 Gy) or fast neutrons (0.05 1.0 Gy) and were observed
for development of mammary carcinoma until 90 weeks of age. The highest dose of all radiation
types resulted in premature cessation of estrous cycling (a phenomenon analogous to menopause in
women) and low cancer incidence in the 1-week groups. Otherwise, the effect of ‫ ﺳ‬rays per unit dose
was essentially similar among the age groups. The effect of carbon ions and fast neutrons, in contrast,
was most prominent when rats were irradiated at 7 weeks. Thus, the three types of radiation impose
breast cancer risk that exhibits distinct age dependence in rats. Relative biological effectiveness(RBE) is a measure for the biological effect of a certain type of radiation as compared with areference, low LET radiation. Mathematical analysis of the above data indicated that RBE values ofcarbon ions and fast neutrons should be separately estimated in animals of different ages. The
estimated values may be taken into consideration in predicting second cancer risk in clinically
relevant situations.

Conclusion
Estimation of the RBE value of accelerated carbon ions and fast neutrons for carcinogenesis is an
important issue in predicting the risk of second cancer after carbon ion radiotherapy. Animal
experiments like ours can offer important information in this regard.

References
Imaoka, Nishimura, Daino et al. (2013) Influence of age on the relative biological effectiveness ofcarbon ion radiation for induction of rat mammary carcinoma. Int J Radiat Oncol Biol Phys
85(4):1134-1140.
Imaoka, Nishimura, Daino et al. (2017) Age Modifies the Effect of 2-MeV Fast Neutrons on Rat
Mammary Carcinogenesis. Radiat Res 188(4):419-425.
Yonekura, Tsujii, Hopewell et al. (2014) Radiological Protection in Ion Beam Radiotherapy. ICRP
Publication 127. Ann ICRP 43(4).

3A13Second cancer after radiotherapy
Jean-Marc Cosset,
Professor and former Head, Radiotherapy Department, Institut Curie, Paris, France
Former vice-chair of ICRP Committee 3
Medical Director, France Amethyst GroupA word of History
Radio-induced cancers were detected very early in the history of Radiology and Radiotherapy: a first casewas reported as soon as 1902 by Frieben, and subsequently, a number of pioneers paid a heavy tribute totheir work with radiation : among them, Marie Curie and Irène Joliot-Curie, whose deaths ( by Myeloblastic
Aplasia and Chronic Myeloid Leukemia, respectively) were clearly related to a whole life devoted to theirstudy of Radiations.
The dramatic consequences of the Hiroshima and Nagasaki bombing, in August 1945, unfortunately
achieved to prove, if necessary, the carcinogenic risks of high doses of Ionizing Radiations. In spite of such
evidence, we have to recognize that, for decades, radiation oncologists did not consider the carcinogenic
risk of their therapeutic irradiations as being a real topic of concern.
The relative lack of interest, for years, of radiation oncologists for the carcinogenic risk of the therapy they
applied, is most probably due to the poor survival results of radiotherapy in the first half of the XXthcentury. Moreover, at that time, a patient surviving more than 5 years was usually considered as being
cured, and his follow-up was stopped (although we now know that most radio-induced cancers are
emerging more than 5, and even 10 - 15 years after irradiation).
It was only in the sixties-seventies that some pioneers clinically detected an excess of second cancers afterradiotherapy. In the eighties, the prominent role of the irradiated volume was demonstrated, as well as thehigher risk of radio-induced cancers in young adults, and even more in children. Today, in 2018, thecarcinogenic risk of any radiotherapy has been extensively studied, and this risk must be kept in mind when
deciding the therapy and when treating the patients.
Second cancers; radio-induced or not ?
The wording “second cancer” needs to be clarified. Cancer unfortunately remains a frequent pathology, and
it is clear that to have been the victim of a cancer does not “protect” against a second one. Moreover, thecause of the first cancer (genetic predisposition, or way of life -see above-) may remain, and may favor the
emergence of a second one.
It is therefore difficult to identify the “second cancer” cases which can be considered as radio-induced, andthose which are clearly not related to irradiation. Up to now, we do not have available, except in rare
specific cases, any specific genetic mutations which would prove the radiogenic cause of a “second cancer”.
The study of large cohorts shed some light on this problem: In the extensive 2007 review by Suit, therelative risk (RR) for a second primary cancer in 11 cohorts of cancer patients was as high as 1.31, whencomparing the radiotherapy patients (RT) and the general population (GP): RR RT/GP = 1.31 ( 95% CI;
1.15 - 1.49 ). It therefore appears that cancer survivors do have a higher risk of developing a “second
cancer”.
However, the real risk of radio-induced second cancers is better evaluated by the RR : “RT/nonRT”, which
compares the cancer patients who received an irradiation to those that did not receive any irradiation. This
relative risk RT/nonRT in the Suit’s study is 1.08 (95% CI: 1.00-1.17). This last RR “RT/nonRT” gives abetter indication of the carcinogenic role (borderline significant) of radiotherapy.
Berrington de Gonzalez , in 2011, concluded , after a large cohort study, that a relatively small proportionof second cancers (about 8% of all « second cancers ») are related to radiotherapy in adults, suggesting thatmost are due to other factors, such as lifestyle or genetics.
Radio-induced cancers: lessons from the literature
A huge number of reviews are now available in the literature, including the one performed by an
ICRP/ICRU task group (unfortunately unpublished to date) and a recent 2017 AAPM document (AAPM
TG 158). From this large experience, can be extracted a few main points:

1/ Cancer patients are at a higher risk for developing secondary cancers than the general population, but see above - radiotherapy is only responsible for a (small) proportion of the second malignancies.
2/ The clinical data emphasize the role of age, with children being much more sensitive to the carcinogenic
effect of ionizing radiations than adults (a 3-6 fold increase).
3/ The reviews of available data confirms the clinical experience, according to which “ the majority of
second induced cancers occur in or close to the high-dose treatment volume” (Hall 2006).
4/ The relative risk appears to be different for different organs, with the thyroid probably being the best
example of an organ particularly sensitive to the carcinogenic effect of radiation, especially in children.
5/ The relative risks of radio-induced cancers tend to be lower in the medical cohort studies than in theJapanese A-Bomb survivor studies (Little, 2001). The fractionation /protraction of most of the therapeutic
irradiations, as well as the neutron component in the A-bomb data may account for this difference(Schneider 2008).
Radiobiological models
The dose/effect model (or risk model) to be used for radio-induction of cancers remains in 2018 a burningand endless topic.
A number of authors stick to the Linear-No-Threshold (LNT) model, whatever the dose, thus from zero Gy
until the large doses of 70-80 Gy of radiotherapy.
The LNT model was mainly derived from the data observed after Hiroshima and Nagasaki, data whichshowed a clear linear relationship between 0.5 and a few grays. This is often considered as the “Goldstandard”, but- Even in the dose range mentioned above, we previously saw that this model, based on atomic bomb
survivors, could overestimate the risk in the medical radiotherapy series.
- For low doses (below 0.5 Gy), radiobiologists are still fighting, some of them sticking to the LNTmodel, some others proposing a threshold (or at least a “practical” threshold, generally about 100
mSv), and finally others describing an underestimation of the risk by the LNT model…
- For “high doses” (above a few grays, but with large variations from a study to another); threemodels are in competition; the LNT one (which would suggest a very high -unrealistic?- risk atradiotherapy doses), the “bell-shaped” model, following data, some as old as 1957 by Gray himself,
showing a decrease of the risk at high doses, and several “plateau” models, where the risk is“plateauing” after a certain dose.
While the battle is not finished, we can only very prudently suggest that the presently available clinical data
seem to better support some “plateauing” at very high doses.
Which recommendations in 2018 ?
The ICRP/ICRU task group and the AAPM TG 158 document proposed recommendations (actually almost
identical) to try and reduce the risk of secondary radio-induced cancers after radiotherapy.
While radiation oncologists and physicists are today well aware of the advantage of reducing the volumes
irradiated at high doses, with more and more sophisticated techniques (IMRT, VMAT, Gating and tracking,
IGRT …), in parallel, it is imperative that those same professionals understand the magnitude of the doselevels outside of the treated volume, and are aware of methods to manage them.
The low doses outside the target volumes have been neglected for too long, and the profession is facing a
new challenge; to reduce as much as possible the deterministic effects, and the carcinogenic risk close to
the target volumes, while reducing at the same time the “low doses” far away from the treated volume, inorder to avoid radio-induced cancers in those areas.
Actually, such a caveat had been well emphasized in ICRP publication 73, subsequently followed by theEuropean Directive 97/43 : « For radiotherapeutic purposes, exposures of target volumes shall be
individually planned; taking into account that doses of non-target volumes and tissues shall be as low asreasonably achievable and consistent with the intended radiotherapeutic purpose of the exposure. »We summarize here the main recommendations for reducing the risk of radio-induced cancer afterradiotherapy:

1. Adapting the irradiation technique- AAPM TG 158 emphasized the trade-off of modern IMRT (Intensity Modulated Radiotherapy)
treatments, relative to 3D CRT. IMRT allows decreased treated volume through increased
conformality, which will reduce the volume of tissue receiving a high dose. However, this is doneat the cost of increased head leakage from increased number of Monitor Units (MUs), which
increases doses farther from the target, and thus the “integral dose” (the total energy absorbed by
the body).
- The more recent VMAT (Volumetric Modulated Arc Therapy) technique is using less MUs, andtherefore allows to reduce the “integral dose”.
- Flattening filter; for both IMRT and stereotactic procedures, the out-of-field dose is reduced when
the flattening filter is removed from the beam line, so FFF (Flattening Filter Free) delivery is an
improvement in terms of reduction of the integral dose.
- Photon energy: here again the radiation oncologist has to face a trade-off between high- and lowenergy treatments. High-energy therapy is associated with some (fortunately low) neutron
production. Low-energy therapy results in higher stray photon dose because of the greater number
of MUs required. Although difficult to precisely quantify, the added neutron contamination at highenergy seem to be offset by the added stray photon dose at low energy. For the AAPM TG 158, theoptimal energy could be an intermediate such as 10 MV.
- Proton therapy allows a substantial reduction in dose distal to the target, resulting in reduced
integral dose (typically by a factor of 2 - 3 compared with IMRT).

2. Reducing the target volumes--

The larger the irradiated volume, the higher the risk of a secondary radio-induced cancer. Reducing
the size of the CTV or PTV can be one of the most potent options for reducing the dose tonontarget structures (AAPM TG 158).
In clinical practice, the CTV has already been reduced in many clinical situations. For Hodgkin's
lymphoma, for example, the former large field irradiation has been replaced in most cases by thetreatment of the involved regions only, with already a positive impact on the risk of radio-induced
cancers. In some other cases, the irradiation of some “prophylactic” lymph node areas could beomitted (For testicular, breast and prostate cancers, for example).
Reducing the PTV margin can be a simple way to decrease the irradiated volume, but one should
keep in mind that such a margin reduction is typically associated with increased imaging (seebelow).

3. Adapting to patient’s age- As previously shown, children are much more prone than adults to develop a radio-induced second
cancer after a given dose of irradiation. There is no “cut-off” for risk depending on age; the risk,
being very high for the newborn, decreases progressively with age.
- In children, when irradiation cannot be omitted, everything should be done to reduce both the target
volume extent and reduce the integral dose.
- In such a setting, proton therapy has been more and more proposed.
4. Adapting to specific organs-

All organs do not demonstrate an equal risk of a secondary radio-induced cancer. Some ofthem, such as the small intestine, are less sensitive to cancer radio-induction, while thyroid
and breast are examples of organs highly sensitive to radiocarcinogenesis, a feature highly
amplified by the age factor (with a high susceptibility in children).

5. Imaging dose management-

IGRT (Image Guided Radiotherapy) has become compulsory when using new highly
precise treatment technologies. However, it brings an additional dose that should not beignored.
Radiation oncologists should be aware of the dose delivered by the IGRT they are using,and should adapt the number of controls to each patient’s case.

6. Other procedures to reduce the risk of radio-induced cancers

-They are based on procedures aiming at reducing as much as possible the “Integral dose”,
and have been presented in detail in the AAPM TG 158 document;-

Avoidance of physical (or mechanical) wedges, responsible for an out-of-field dose higher by afactor of 2 - 4 relative to an open field, use of tertiary Multi Leaf Collimators (MLC), choiceof the beam angles, jaws tracking, patient shielding, and accelerator shielding are othersolutions to reduce the integral dose.
Conclusions
Even if radio-induced cancers are rare, they must be kept in mind each time radiotherapy is proposed.
It had been pointed out that new technologies, such as IMRT, were responsible for an increase in the (low)doses received out of the field. Fortunately, such a dose increase at distance is largely offset by the verysignificant reduction of the areas receiving high doses (areas where the risk of radiocarcinogenesis is muchhigher). Finally, even if new technologies were not considered to cause more second radio-induced cancers
than conventional techniques, a continual effort should be made to reduce the out of field doses delivered topatient(s) as a continued radiotherapy improvement strategy, thus following previous ICRP
recommendations concerning optimization.
Age is one of the key parameters impacting on the risk of radio-induced secondary malignancies. Children
could be nearly 3 to 6 times more sensitive to the carcinogenic effect of radiation than adults. Consequently,
all efforts should be made to reduce the risk in children. In contrast, the second cancer risk is much lower,
or even nil, in the elderly. In between, the secondary cancer risk, although most often low, should be kept inmind when designing therapeutic schemes and/or prescribing a specific irradiation.

3A22
Low-dose CT screening for lung cancer
Takeshi Nawa, MD
Division of Respiratory Medicine. Hitachi General Hospital, Ibaraki, Japan

Lung cancer is a leading cause of cancer death in Japan. Though smoking is thegreatest risk factor for lung cancer death, Asian have a relatively high risk of lungcancer among nonsmoker compared to the Caucasian. In addition, nonsmoker’s lungcancer is increasing in Western countries. Since the risk of lung cancer due tosecondhand smoke has also been reported, death from lung cancer is a serious issue
regardless of smoking history.
Lung cancer screening using low dose CT (CT screening) was initiated in Japan,
United and in Europe around early 1990's. It was reported that many earlier, smallerlung cancers can be detected by CT screening compared with conventional chest X-ray.
In 2011, National Lung Screening Trial (NLST) reported that annual CT screening forhigh risk participants leads to 20% reduction of lung cancer death1). Recently, European
position statement on lung cancer screening recommended that European states
demand to determine a timeline for implementing lung cancer screening2). There is apossibility that CT screening for high risk participants will be spread in westerncountries.
Though the effectiveness of CT screening for nonsmoker and light-smoker is still
unclear, CT screening in Japan has been provided to people other than heavy smokers.
The results of ongoing randomized controlled trial (JECS study) are expected3). In
addition, it is desirable to evaluate the results of screening by observational studies.
In Hitachi City, Ibaraki Prefecture, CT screening for 50 years or older citizens initiatedin 1998, and 30% of the citizens received CT examination at least once by 2006. We
reported excellent survival (5-year survival of 90%) of 210 cases of lung cancer detectedby CT screening. Furthermore, based on time trend analysis, a significant reduction(24%) in lung cancer mortality was observed 4 to 8 years after introduction of CT
screening among Hitachi residents4). This finding suggests that wide implementation of
CT screening can decrease lung cancer mortality at community level. Currently, we areconducting a cohort study of CT screening participants and X-ray screening participants
among Hitachi residents.
CT screening images can detect various smoking related findings represented by thepulmonary emphysematous change (CT emphysema). We reported that CT emphysema
is an important radiological risk factor for future abnormality of respiratory function. If
we can evaluate the risk of respiratory disease and comorbidity according to the images,
the benefit of screening is expected to further increase.

References
1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with
low-dose computed tomographic screening. N Engl J Med. 2011 Aug; 365 (5) :395-409.
2. Oudkerk M, et al. European position statement on lung cancer screening. Lancet
Oncol. 2017 Dec; 18 (12): e754-e766.
3. Sagawa M, et al. A randomized controlled trial on the efficacy of thoracic CT
screening for lung cancer in non-smokers and smokers of <30 pack-years aged 50–64
years (JECS Study): research design. Jpn J Clin Oncol. 2012;42:1219–1221.
4. Nawa T, et al. A decrease in lung cancer mortality following the introduction of
low-dose chest CT screening in Hitachi, Japan. Lung Cancer. 2012 ; 78(3) : 225-8.

3A23
Development of Low Dose Diagnostic CT
Takashi Tanaka
Senior Manager, Canon Medical Systems Corporation
Since the first diagnostic CT scanner was produced in 1972, its performance has been
continuously improved by series of innovations, such as helical scan technique,multi-slice detectors, ECG gating scan, sophisticated reconstruction algorithm, andso on. These innovations enabled many new scan techniques which could provide us withnew or more accurate diagnostic information. On the other hand, some of them suchas cardiac gating scan, dynamic hepatic scan, and perfusion scan require higher
radiation dose. As the total number of CT scans increases, the associated risk ofradiation became a social concern. Canon Medical Systems (formerly Toshiba Medical
Systems) has been developing and manufacturing CT systems over 40 years. Throughout
its history, we have been continuously introducing new technologies to reduceradiation dose so that new scan techniques could be clinically acceptable and thus
expanded the clinical value of CT systems. Followings are examples of suchtechnologies:(1) higher output with lower noise from detectors to achieve better SNR in raw data.
(2) X-ray tube current modulation to dynamically control X-ray output depending on
the body thickness, heartbeat, and breathing cycle.
(3) active collimation to shield X-ray at the scan start and end position in a helicalscan which does not contribute to output images.
(4) dynamic scan condition control to adjust scan parameters during a helical scandepending on the patient body part(5) iterative reconstruction algorithm to achieve higher resolution while reducing
image noise by introducing various physics models into the reconstruction algorithm
We continue our research and development to enhance capability of a CT scanner while
reducing the radiation dose and thus expand its clinical value.

Abstracts of Poster Presentations

P01

The influence of low dose-rate radiation on the mutation frequency in Drosophila: Tomonori Onishi (Kansai University)

P02

Two-step model for the occurrence of retinoblastoma: Tetsuhiro Kinugawa (Kansai University)

P03

Analysis of Childhood Thyroid Cancer Incidence in Fukushima based on Dose Response
Relationship: Takahiro Wada (Kansai University)

P04

Agendas and Issues of Participatory Dialogues by Junior-High and High School Students
from Fukushim Hama-doori and Capital Area - "Exciting Class 2017" by Junior- and HighStudents on Thyroid Screening Test - Issues and Results of IWAKI Dialogues –: Tetsuo Sawada (Tokyo Tech.)P05

The development of ESR dosimetry using human hair
: Seiko Hirota (Hiroshima Univ. RIRBM)

P06

Particle Therapy System Simulation Framework and its application for probing material
composition in patient body
: Tsukasa Aso (National Institute of Technology, Toyama College)

P07

Twitter analysis of public response to radiation exposure after the Fukushima Daiichi
Nuclear accident: Kazuko Uno (Louis Pasteur Center for Medical Research)

P01
The influence of low dose-rate radiation on the mutation frequency
in DrosophilaTomonori Onishi1, Takahiro Wada1, Yuichiro Manabe2 and Masako Bando31
Kansai University, 2Osaka University, 3RCNP, Osaka University
 In 1927, Muller1) first reported that the artificial mutation frequency in Drosophila increased
linearly with the total dose of X-ray irradiation. Later, it was found that the slope of this linear
increase did not depend on the dose rate of the X-ray. In contrast to these results in Drosophila,
Russel2) found in his Mega-mouse project that the mutation frequency in mice depends on the dose
rate as well as on the total dose.
 Now, we know that there are repair mechanisms against the damages to DNAs. In order to analyze
the experimental data on the mutation frequency with chronical exposures, we need a theoreticalframework which takes account of the repair (recover) mechanisms. We analyze the experimental
data of the mutation frequency in Drosophila which was done by Purdom and McSheehy3) using amathematical model, Whack-A-Mole (WAM) model, which takes account of the recover effects.
 In WAM model, the mutation frequency is described with the following differential equation.
𝑑𝐹𝑑𝑡=𝑎0+𝑎1𝑑−(𝑏0+𝑏1𝑑)𝐹
Here, 𝐹 is the mutation frequency, the term 𝑎0+𝑎1𝑑 is the rate of change from normal cells tomutated cells, and the term 𝑏0+𝑏1𝑑 denotes the decrease rate of mutated cells.
 Purdom and McSheehy irradiated male Drosophilawith both acute and chronical exposures with the15same total dose (800rad). In the case of low dose-rate
exposure (0.05 rad/min), the irradiation extended over M
the development period from larvae to adult. In the ut
10case of high dose-rate experiments (0.5 rad/min and ati
on
5.0 rad/min), in order to compensate the effects of thedevelopment during the chronical exposure, they fre
divided the samples into several groups then each qu 5group was irradiated sequentially through the endevelopment period. Even with the same given dose cy
with the same dose rate, the mutation frequency [0
becomes smaller as the interval becomes longer. Even %
]with the same given dose with the same dose rate, theCagesmutation frequency becomes smaller as the interval
becomes longer. By taking account of the interval
Fig.1
Comparison
betweenbetween the exposure and the mating.
We could reproduced the data. We found that it isimportant to take account of the difference in theradiation sensitivity between the germ cells and thespermatogonia cells.

experimental data (bar graph) andtheoretical value (line graph) for
Broodsample of 6 cages with 0.5
rad/min irradiation.

References
1) H.J. Muller Science, 66, 84-87 (1927)
2) W.L. Russell and E.M. Kelly, Proc. Natl. Acad. Sci. USA
79, 542-544 (1982)
3) C.E. Purdom and T.W. McSheehy, Int. Jour. of Radiation Biology, 7 (3), 265-275 (1963)

P02
Two-step model for the occurrence of retinoblastoma
Tetsuhiro Kinugawa1, Takahiro Wada1 & Yuichiro Manabe2
Kansai University (Japan)1, Osaka University (Japan)2
It is widely accepted that cancerization is caused by the accumulation of gene mutations (Knudson hypothesis [1]).
We propose a mathematical model which describes the occurrence of retinoblastoma on the basis of Knudson
hypothesis. According to Knudson hypothesis, mutations of both genes called Rb1 are required to develop
retinoblastoma. Retinoblastoma can be classified in two categories, hereditary and nonhereditary cases. As
hereditary cases already have one mutated Rb1 gene, one mutation of the other Rb1 gene is required, while twomutations are required in nonhereditary cases. Considering this difference between the two categories, we propose
a mathematical model named “two-step model”, which expresses the sequence of gene mutations required todevelop retinoblastoma.
𝑑𝑁0𝑑𝑡=−𝐴0𝑁0

𝑑𝑁1𝑑𝑡=𝐴0𝑁0−𝐴1𝑁1𝑑𝑁2𝑑𝑡=𝐴1𝑁1(1)

In equations (1), Nj (j=0,1,2) denote the numbers of cells which have j mutated Rb1 genes. N2 corresponds to cancer
cells. In hereditary cases, cancerization of cells initiates from N1, while it starts from N0 in nonhereditary cases. Aj
represents the mutation rate from Nj to Nj+1.
Using maximum likelihood method, we determined the parameters so as to match the solution of equations (1) tothe epidemiological data [2]. Initial values of the Nj are determined by taking account of the frequency of thedisease. We also included a term which represents the natural decrease of the cells. The results of the two-stepmodel are shown in Fig. 1 in comparison with the epidemiological data.

Fig. 1 Comparison between the epidemiological data and the results of the two-step model. Boxes
express the epidemiological data, and crosses indicate the results of the two-step model

The two-step model succeeded at representing the qualitative difference between hereditary and nonhereditarycases. However, the two-step model didn’t reproduce the peak of the epidemiological data in nonhereditary cases.
We will look for more epidemiological data of retinoblastoma so that we can improve our model.
References[1] Knudson, A. G. (1971) Proc. Natl. Acad. Sci. USA 68, 820-823[2] Hethcote, H. W. & Knudson, A. G. (1978) Proc. Natl. Acad. Sci. USA 75, 2453-2457

P03

Analysis of Childhood Thyroid Cancer Incidence inFukushima based on Dose Response Relationship
Takahiro Wada1, Hiroshi Toki2, Yuichiro Manabe3, Toshihiro Higuchi4, Masako Bando2
1: Dept. of Pure and Applied Physics, Kansai University, 3-3-35 Yamate-cho, 564-8680 Suita, Japan
2: RCNP, Osaka University, 10-1 Mihogaoka, 567-0047 Ibaraki, Japan
3: Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, 565-0871 Suita, Japan
4: School of Foreign Service, Georgetown University, Washington DC, 20057, USA

Environmental radioactive contamination caused by the Fukushima Dai-ichi Nu-clear Power Plant accident has
aroused a great concern regarding a possible in-crease of the incidence of childhood thyroid cancer. The
ultrasound examinations conducted as part of Fukushima Health Management Survey (FHMS) provide us withvaluable information. FHMS is a key to investigating the health risks caused by low-dose radiation exposure atlevels which are estimated to be far lower than those from the Chernobyl accident. FHMS is divided into thepreliminary base-line survey (PBLS) and the full-scale survey (FSS), and some of their outcomes are reported
regularly and made available to the public. We investigate the dose-response relationship concerning the PBLS
and the FSS by using information on the distribution of radioactive Cs isotopes (134Cs and 137Cs) and 131I in soil
and also that of air dose rates. Comparison of these results suggests that the behavior of the dose-cancer
incidence curve based on the FSS data shows a different structure from that of the PBLS data.
There have been several papers on the incidence of thyroid cancer after the accident, which drew markedly
different conclusions regarding an association between incidence of thyroid cancer reported in Fukushima andlow-dose radiation exposure. [1] In this paper, we emphasize the importance of investigating the dose-response
relationship quantitatively. Fortunately for our purpose, we have detailed deposition maps of gamma-ray
emitting radioactive nuclides in eastern Japan based on extensive soil sampling in addition to air dose
measurements conducted shortly after the Fukushima accident. [2] We group neighboring municipalities withsimilar radiation levels so that each area has the child population large enough to contain a meaningful numberof thyroid cancer cases. Based on the analysis of both populations and dose distributions, the whole prefecture
is divided into six areas. We perform a Poisson regression analysis with a straight line N = ax + b with x being
the air-dose rate or the amount of 131I in soil and N being the number of cancer cases per 105 people.
The results are summarized as follows.
(1) We found a negative correlation for the thyroid cancer case in the PBLS with the dose distribution. The 95%

confidence interval contains the case of no correlation.
(2) We found a positive correlation for the thyroid cancer case in the FSS with the air-dose distribution. The

probability of positive correlation in the likelihood distribution is 94.5%.
(3) We found a positive correlation between the thyroid cancer cases in the FSS and the amount of

131

I, but the

AIC value indicates that this correlation is smaller than that of the air dose rate.
We found a positive correlation between the thyroid cancer case reported in the FSS and the radiation doses,with the association stronger with external exposure than with internal one. It is important to continue the studyof the dose-cancer relationship as more data are available.
References:[1] Tsuda T, Tokinobu A, Yamamoto E, Suzuki E, Epidemiology 27 (2016) 316;
Ohira T, Takahashi H, Yasumura S et al, Medicine 95 (2016) 35.
[2] Saito K, Tanihata I, et al., Journal of Environmental Radioactivity 139 (2015) 308.
Acknowledgements This work was supported by JSPS KAKENHI Grant Numbers JP16H03094, JP16H04637,
JP15K12204, JP15K14291

P04
Agendas and Issues of Participatory Dialogues by Junior-High and High SchoolStudents from Fukushim Hama-doori and Capital Area
- "Exciting Class 2017" by Junior- and High Students on Thyroid Screening Test - Issues andResults of IWAKI Dialogues –Tetsuo Sawada1*Chieko Nakayama2Natsumi Kimura3Atsushi Koori
1Tokyo Tech., 2Kanagawa Univ. High, 3Tohoku Univ., 4Iwaki High School*
Tel&Fax: (+81) 3-5734-3062; E-mail: tetsuo@nr.titech.ac.jp
In response to the results of the incandescence classroom 2016 conducted in Tokyo in December
2016, at the end of April 2017, about 20 students of Iwaki High School and Kanagawa University
High School had a dialogue at Iwaki High School with the schedule of an overnight stay. As a result,they derived 20 items in three issues. They are: 1) things I would like to ask the expert (12 items), 2)
what I would like to discuss with everyone (4 items), and 3) opinions (4 items).
1. Introduction
In December 2016 in Tokyo, the "Incandescence Classroom 2016", which is a place of participatory
dialogue on thyroid inspection conducted for children in the whole area of Fukushima prefecture,with the aim of constructing an authority related to nuclear power and radiation. In response to theparticipation of high school students at that time, "Iwaki Dialogue -- Incandescent Classroom 2017"
was held at Iwaki High School to aim for deepening the dialogue.
2. Issues, methodology, and results
1) Issues and objective
Under the four indicators of Socio-Scientific Issue (SSI) (training of citizens awaiting
scientific knowledge, introspective development of social responsibility, intuition andlogical discussion, demonstration of critical thinking), we aimed to raise the dialogue
capability and create a sprout of collaborative engagement. Also Iwaki Dialogue aimed tovisualize issues with publicity through dialogue and lead to advocacy (promotion of public
policy formation).
2) Design of opportunity or methodology
According to "incandescence classroom 2016" [1, 2, 3], the dialogue conversation andvoluntary facilitation were the major components of the methodology. Two female highschool students became the main facilitator, and conducted a dialogue of three sessions overtwo days.
3) Results
Table 1 12 items for expert knowledge
By the two-day dialogue, the question of 12
items shown in Table 1 was summarized. In
addition to this, four items which they want todiscuss with everyone: 1) the necessity to divide
A1, A2, 2) thyroid meal diet - its development,3) how to disseminate delivery classes, 4)measures to prevent lowering of the examination
rate. Four opinions were derived: i) global
standards should be set for the thyroid test, ii)
thyroid test should be included in conventional
health examinations, iii) implementation in otherareas, and iv) data comparison with other areas.
In 2), there was a sprouting of cooperative
engagement.
3. Conclusion
Based on information sharing and introspective
thinking in high school students, high school
students gather what they want to know (expertise),what they want to talk about, and opinions. Next is finally going into the phase of providing
expert knowledge.
References: [1-3] AESJ Proc. 2017 Annual mtg., 2C13-15

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P06
Particle Therapy System Simulation Framework and its application
for probing material composition in patient body
Tsukasa Aso1 , Keiichiro Matsushita2, Teiji Nishio3 and Shigeto Kabuki4
1

National Institute of Technology, Toyama College; 2Kyoto Prefectural Univ., Radiology; 3Tokyo
Women’s Medical Univ., Medical Physics; 4Tokai Univ., School of Medicine, Radiation Oncology
The reliable dose control has been so far approached by improving the dose calculation
algorithms1,2. However, the use of secondary gamma-rays via nuclear interactions inside patientbody is of interest for monitoring the irradiation field during the treatment. The project, “Tumor
Response Observation System for Dose-volume delivery Guided Particle Therapy, TROS-DGPT”,
has been developing a hybrid beam online PET and Compton Camera system (HBOLP/CCs)3 forthis purpose. Such gamma rays reflect not only the irradiation field but also the material composition
inside patient body. The experimental analysis of positron emitter nuclei production and thetreatment site has been firstly reported by Miyatake et al.4 It used the beam on-line PET system
mounted on a rotating gantry port (BOLPs-RGp) at the National Cancer Center, Kashiwa5. In thispaper, we studied the prompt gamma-ray energy spectra in various material target by using Monte
Carlo simulation. We describe about the functions in the Geant46 based particle therapy systemsimulation framework, PTSIM7-8, and its application for probing the material composition in thetarget.
The PTSIM is a single application software for simulating interactions of particle with matter. It
was originally developed for calculating dose profiles inside patient and validating treatment plans in
proton and carbon therapy facilities. The functions were extended according to the updates oftreatment techniques including the imaging devices for the irradiation field monitoring.
In this study, the simulation was performed for 190 MeV proton beam with a target inhomogeneous material. The size of target was set to 30 cm square and 50 cm depth. The material waschosen from polyethylene (C2H2), water (H2O), acrylic (C5H8O2) and a soft tissue material in Geant4(G4_MUSCLE_WITH_SUCROSE). These materials are categorized as carbon enriched, oxygen
enriched or admixture of carbon and oxygen elements with different mass fractions. The
gamma-rays generated via nuclear interactions were detected at the simple tabular detector aroundthe target. The energy distributions were compared among the target materials.
Several energy spectra were observed in the energy distributions such as deexcitation states of 12C(4.4MeV), 14C(2.3MeV), 15O(5.2MeV), 16O(6.1MeV, 6.9MeV, 7.1MeV). The results of thecorrelation between the materials and the spectra are reported at the conference.

Acknowledgements
This work was supported in part by Japan Science Technology Agency (AMED), Development of Advanced Measurement andAnalysis Systems (AMED-SENTAN) program.

References
1) Paganetti H, Jiang H, Lee S Y and Kooy H M: Accurate Monte Carlo simulations for nozzle design commissioning and quality
assurance for a proton radiation therapy facility, Medical Physics 31(7), 2107-2118, 2004.
2) Reynaert N, Marc S C, Schaart D R, et al.: Monte Carlo treatment planning for proton and electron beams, Radiation Physics
and Chemistry 76(6), 643-686, 2007.
3) Nishio T: Innovative proton therapy with irradiated volume image by target nuclear fragment reaction, RIST News No. 50,
24-35, 2011.
4) Miyatake A, Nishio T et al.: Measurement and verification of positron emitter nuclei generated at each treatment site by target
nuclear fragment reactions in proton therapy, Medical Physics 37(8), 4445-4455, 2010.
5) Nishio T, Miyatake A, et al.: The development and clinical use of a beam ON-LINE PET system mounted on a rotating gantry
port in proton therapy, Int J Radiat Oncol Biol Phys 76(1), 277-286, 2010.
6) Agostinelli S, Allison J, Amako K, et al.: Geant4 – a simulation toolkit, Nuclear Instruments and Methods, A506(3), 250 -303,
2003.
7) Akagi T, Aso T, Faddegon B, et al.: The PTSim and TOPAS Projects, Bringing Geant4 to the Particle Therapy Clinic, Progressin Nuclear Science and Technology, Volume 2, 912-917, 2011.
8) Akagi T, Aso T, Iwai G, et al.: Geant4-based particle therapy simulation framework for verification of dose distributions in
proton therapy facilities, Progress in Nuclear Science and Technology, Volume 4, 896-900, 2014.

P07
Twitter analysis of public response to radiation exposure
after the Fukushima Daiichi Nuclear accident*Kazuko Uno1, Masaharu Tsubokura2, Yosuke Onoue3, Saori Kobayahsi3, Hitoshi
Fujimiya4, Hiroyuki A. Torii5 (1Louis Pasteur Center for Medical Research, 2Soma
Central Hospital & Minami-soma Municipal General Hospital, 3Science for Innovation
Policy Unit, Center for the Promotion of Interdisciplinary Education and Research,
Kyoto University, 4Dynacom Co., Ltd., 5School of Science, The University of Tokyo)

In the aftermath of the Fukushima Daiichi nuclear disaster, there was confusion among
citizens in Japan about the effects of radiation, due to a flood of contradictory opinions,particularly on social media. Our aim is to identify the source of information and how it
spreads on social media so this information can lead to improvements in crisis
communication during large-scale disasters. Twitter data was purchased amounting totwenty-five million tweets. Tweet contents were related to radiation in Fukushima and weresent out from March 1st to September 15th, 2011. We analyzed this Twitter data to see if andhow tweets influenced public reactions.
The top 100 influencers, the individuals who had the greatest impact on the spread of
relevant information, were categorized in three groups based on the contents of their tweets.
Group A consisted on influencers whose tweets about radiation were based on relevantscientific evidence; in group B, the majority sent out cautionary messages thatover-emphasized or exaggerate the danger of radiation. Group C consisted mostly of
influencers who were media related.
Data showed that influencers within each group often retweeted each other. As well, we
noted that tweets generated by group B influencers accounted for the majority of retweets
one month after the disaster. Group B did not lose its majority share of re-tweets even after
six months after the nuclear incident. We speculate that group B maintained its dominancebecause of the higher number of mutual mentions among the influencers in the group, andwe verified this hypothesis using network analysis. Results indicated that the density ofconnection among the influencers is relevant to the ease with which information spreads.
Further research is necessary to understand how to effectively convey scientific but notemotional information through SNS.

Abstracts of High school Special Session

HSS01

Dose rate mapping project by students for the creation of a better future: TEAM YURIKAMOME

HSS02

The special quality of the radiation meter and radiation measurement around the
Fukushima Daiichi nuclear power plan
: Kitasuma Senior High School, Hyogo

HSS03

Trial of the Discussion about Radiation at Kyoto Girls' High School: Kyoto girls' high school, Kyoto

HSS04

Radiation measurement of stones in historical sites and building materials in Kyoto: Rakunan High School, Kyoto

HSS05

What is the meaning for us to keep on choosing nuclear power plants?
: Tokyo Gakugei University International Secondary School, Tokyo

HSS06

The Investigation of the Decontamination Methods and the Impression of Fukushimafrom Overseas: Adachi High School, Fukushima

HSS07

Expanding for Cooling Area Range of Peltier Cooling Type Cloud Chamber: Adachi high school, Fukushima

HSS08

The Changes in Harmful Rumors about Fukushima in the Newspapers immediately after
Fukushima Daiichi Nuclear Disaster in 2011.
: Adachi High School, Fukushima

HSS09

Individual dose measurement by using D-shuttle: the study of values of outliers measured
in the dosimeter and the discussion of dose restriction: Fukushima High School, Fukushima

HSS01
Dose rate mapping project by students for the creation of a better future.
TEAM YURIKAMOME
Imagine a bowl of hot water of 80 degrees centigrade placed just in front of you. You would feelthe steam and heat; and you would instantly judge that you must not carelessly touch it. Thisjudgement of yours is derived from your experiences, not by your pure instinct. You learn thedanger of hot water as a child through your body experiences: water could be hot or cold, and it
could burn you when it is too hot; and the burning could be serious. And also we have, in our daily
lives, many opportunities to measure temperatures of our bodies as well as of water withthermometers. Our learning through experiences enables us to immediately see the danger ofboiling water.
We would suggest that the same experience-based learning should be applicable to our learning ofradiation. Last year, the radiation-mapping project by pupils at elementary school and students atjunior and senior high school: “TEAM YURIKAMOME [Black-headed Gull]” have started with thisidea.
TEAM YURIKAMOME website:
Japanese: https://sites.google.com/view/yurikamome/
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HSS03

Trial of the Discussion about Radiation at Kyoto Girls' High School
ISHIDA Akari, KATAOKA Ami, KUBOTA Saki,OOTSUKA Akane, OKUMURA Erika,   
OKUMURA Sayaka, TORII Chitose
Kyoto girls' high school

1. Introduction
What is "radiation"? It is difficult for us to think about radiation problem
because we don't know well about radiation and we have an image that radiation issomething horrible.
But discussing social problems with each other must be meaningful for us. So, we
had the discussion program to think about radiation problems. We report how we
discussed and how we felt.
2. Method
About 80 students of Kyoto girls' high school took part in the discussion. In
advance eight members of them including us looked into two themes. One is "Do
you receive radiation treatment?" The other is "Do you continue to use nuclear
power plants?"
We presented both favorable and unfavorable opinions and evidence. After hearing
about the opinions, all of the students discussed how they think.
3. Result
We have a discussion on 15th March, so we don't know how the trial result now.
We will be able to report the result on BER 2018. Please look forward to our report!

The look of discussion of the past (2013)


HSS04
Radiation measurement of stones in historical sites and building materials in Kyoto
Rena MIYAOKA†, Yuichi TSUNOYAMA§†

Rakunan High School, §Radioisotope research center, Kyoto University

It is well known that radiation dose emitted from stones varies depending on the amount ofradioisotopes and radioactive nuclear species contained in the ore. In our city “Kyoto”, There are
famous temples and shrines built in hundreds of years ago. In such historical places, stone statues
for people's beliefs are often built. We have measured the radiation dose rate in the immediate
vicinity of some of those stones. Interestingly, in some stone statues, the dose rate was several
times higher than the background (Fig.1). From ancient times, Japanese may have been praying ofstones which radiation is slightly higher as object of faith ☺
Our results of measurement will be reported.

HSS05What is the meaning for us to keep on choosing
nuclear power plants?
Marie Kurasawa, Aoba Hori, Jyuri Manabe, Masanobu Furuya, Tomomi Samejima
Tokyo Gakugei University International Secondary School*

Tel: (+81) 3-5905-1326/Fax: (+81) 3-5905-0317; E-mail: vegeetam@u-gakugei.ac.jp

Before the Fukushima daiichi nuclear disaster that happened around 7 years ago, 30%
of Japan’s electricity was generated by nuclear power plants. Currently, that number has
been kept low to approximately 2%, but there are still arguments both for and against.
We have been investigating the reality of nuclear power plants and analyzing the viewsof people with different perspectives in order to understand why Japan has kept onchoosing nuclear power plants. Our final goal is to stop the harm the nuclear power
plants bring on people and to create a society that chooses its energy source more
responsibly, while understanding the flaws of nuclear power plants. The premise is that
if we are using electricity that is generated by nuclear power plants, we are “choosing”
to use them. However, the reality is that we do not have enough decent information
about this situation and that we, as individuals, aren’t aware that we are “choosing”.
Thus, this year we analyzed the situation of nuclear power plants by interviewing
people with different points of view, and sought to find an effective way to present thissituation and actually presented as well. Through the results of the survey we took fromstudents before and after the presentation by the filmmaker Hitomi Kamanaka,
interviews from a variety of people, and our research on this problem from a scientificpoint of view, we are finding out that we are choosing to use nuclear power with limited
knowledge and little consideration.

HSS06The Investigation of the Decontamination Methods and the Impressionof Fukushima from Overseas
Yuka Shinotsuka1, Shinya Ishii1
1

Fukushima Prefectural Adachi High School

The leading clean up program of radioactive contaminated area of Fukushima is decontamination, which is toremove the surface of the soil with radioactive cesium. Generally, the scrapped soil is buried underground andcovered with no contaminated soil, because the air does rate due to radioactive substances such as radioactive
cesium decreases by shielded by the soil. I confirmed the fact by experiment. First, the radiation source which ismantle of camping lights lanterns was laid down on the bottom of a plastic container whose depth is about 5 cm
and I measured the air does rate by gyorogeiger which is GM counter around the top of the container. Next, plastic
bag which was packing the no contaminated soil and whose height was about 4 cm. The plastic bag was put on theradiation source, and I measured the air does rate again around the same point. The air does rate changed from
0.51 µSv/h to 0.24 µSv/h. The contaminated school ground has been buried at the range from 150cm to 90cm
underground. Because of he decreasing effect of the air does rate by the shielding the soil and by taking a distancefrom contaminated soil, the air does rate of the ground is about 0.11 µSv/h today.
I made a presentation about this at the Environment Creation Symposium on March. The words that were told
from overseas at the time of the symposium remained impressive. He said that he was asked, “Can people lice inFukushima?” in USA. It was not only a shock for me, but also what made me think at that time. Now, I haveinvestigated the impression of Fukushima from overseas by the Internet. I’d like to discuss this, too.

HSS07

Expanding for Cooling Area Range of Peltier Cooling Type Cloud Chamber
Aoi Mutoh
Fukushima Prefectural Adachi high school
Through our activities to convey the current situation of the Fukushima Prefecture and tointeract with students from other prefectures, I learned that few people feel there is radiation in
everywhere, not only in Fukushima and have the perception that the whole area of Fukushima
prefecture is safe. To change this situation, we would like to inform that there is naturalradiation everywhere, as a first step. To achieve it, we guess a cloud chamber that we canobserve natural radiation is effective. We want to demonstrate the experiment of the cloud
chamber and compare between Fukushima and other area.
So far, we have made a cloud chamber using Peltier and CPU cooler in order to improve
portability and convenience. However, we can hardly observe natural radiation, because thecooling area range of Peltier elements is narrow, only 16 cm2. So we have been trying to
expanding by using copper plate and increasing the number of Peltier elements.

Fig.1. System of the Peltier coolingFig.2. Alpha-rays track observed by ourtype cloud chamber.

system.The source is monazite ore.

HSS08The Changes in Harmful Rumors about Fukushima in the Newspapers immediately after
Fukushima Daiichi Nuclear Disaster in 2011.
Mirai Kanomata1, Shinya Ishii1 ・★

（２）

.

1

Fukushima Prefectural Adachi High School
応 し 物 地 指民 原

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It has been 7 years since Fukushima
accident
year, harmful rumors about Fukushima still
求 う が nuclearて る 物 thisで を の め
避 か 直Daiichi
る な 難 い に 深 ︒ 日
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hope
harmfulwill
相 い のI にで ま事 電 震be heard if a similar accident
風 never
へ 手 者 rumors
緊 たthat
加 径 ago.
ス 域 内

occurs.

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生 vegetables or fruits from Fukushima.
bullying to evacuated children from Fukushima and boycotts

For example,
Especially,活
the harmful rumors just after the accident, I am interested in, effected directly to the life of victims. One
物
example, doctors’ support team from Tokyo heading for Miharu
town in Fukushima changed its destination into
資を が 能 や 続 済 炉
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域 風 う いた ﹁う 民 求 が け な な
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と 無 仕 か ﹁
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い﹂ し の 向 はに Ｈ 最 五 木 リ 陸 験 をと が が︑莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢莢

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れ 九 県 挙 月 合 特

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い ま の でる 月 議 を 以 ︑ 例 県 た 川 回 選 予 議を ︶ ホ び る ト 念 を 六 強 ﹁ ３ れ が県 の﹂ で が プと ご 選 行 上 法 法 選 ︒ ︑ 答 挙 定 選
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や テ ッ が こ 風
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HSS09
Individual dose measurement by using D-shuttle: the study of values ofoutliers measured in the dosimeter and the discussion of dose restriction
Fukushima High School:
AYAME Ishida, YUKINO Kikuchi, SHO Fukuda, REO Takahashi
Abstract
Since 2014, after the Fukushima Daiichi Nuclear Accident, we have conducted themeasurement of individual radiation dose by using a dosimeter called D-shuttle, bywhich we compared the data of people inside Fukushima, outside Fukushima andoverseas. Even though the result shows that dose rate of people in Fukushima is as low
as that of people outside Fukushima and overseas, the values of high-dose “outliers”
measured in the measurement are not clear, which we could find out one of the causes ofsuch “outliers.” Also, during the measurement, we have found that the values ofindividual dose measured with D-shuttle are quite smaller than we expected. Comparing
the data, we have realized that the dose restriction value designated by the government,
0.23Sv/h (a calculated value based on the restriction by the ICRP’s Recommendation,
1mSv/y) is an overestimated one, by which the decisions of decontamination work insome municipalities were made, and cost a lot.
1. Objective- To find out what causes the values of high-dose “outliers” in the D-shuttle measurement- To compare dose rate measured by air dose monitoring with individual dose measuredby D-shuttle
2. Method- To check whether anti-shoplifting sensors have some effects on the data of D-shuttle- To compare the data of air dose and individual dose in the same conditions such asplace or time
3. Result- One of the causes of the values of high-dose “outliers” is the reaction to anti-shoplifting
sensors- Individual dose of people in Fukushima is as low as that of people outside Fukushima
and overseas, and the values of individual dose measured with D-shuttle are quite
smaller than we expected
4. Discussion- The result that the values of high-dose “outliers” are caused by anti-shoplift sensors
confirms that the individual dose collected in the D-shuttle measurement in Fukushima
is as low as that of other areas, and also that the Fukushima Daiichi Nuclear accident
did not affect the individual dose of people in Fukushima seriously.

- The other result that the values of individual dose measured with D-shuttle are quite
smaller than we expected implies the decisions made by the government should be basedon individual dose in the case of nuclear disasters, as the Fukushima’s case shows theover-estimate of the dose, by which some social problems were caused.
5. Conclusion- The individual dose in Fukushima we measured after the Fukushima Daiichi Nuclear
accident is much smaller than we expected. Judging from this data, the designated value
by the Japanese government, 0.23Sv/h (based on the ICRP’s Recommendation), is anoverestimated one, considering resulting social problems such as the high cost of
decontamination work or the collapse of communities. This should be one of the lessons
to be learnt from the Fukushima’s case.

Host
Multidisciplinary research on biological effects of radiation,
Committees for Research Promotion in Specialized Areas,
Japan Society for the Promotion of Science
Research Center for Nuclear Physics (RCNP),
Osaka University
Interdisciplinary platform for biological effect of radiation,
Collaborative Research Projects,
Graduate School of Engineering,Osaka University
Department of Pure and Applied Physics,
Kansai University
CASNET
organized by NPO Einstein
Sponsor
The Tokyo Club