14th INTERNATIONALTHYROID CONGRESSP A R I S , P A L A I S D E S C O N G R È S

1 1 - 1 6 S E P T E M B E R 2 0 1 0

Information, Registration, Exhibition:

ITC 2010 / MCI24 rue Chauchat75009 Paris, FranceTel: +33 (0)1 53 85 82 80Fax: +33 (0)1 53 85 82 83Email: itc2010@mci-group.com

EuropeanThyroid

Association

AmericanThyroid

Association

Asia & OceaniaThyroid

Association

Latin AmericanThyroid Society

A meeting co-organised by:

ww

w.it

c201

0.co

m

SAVE THE DATE!

F I R S T A N N O U N C E M E N T

annonce1 12/08/08 12:18 Page 1

14th International Thyroid Congress

Paris, Palais des Congrès

11 – 16 September 2010

ITC 2010

Selection of abstracts

W E L C O M E L E T T E R C O N G R E S S S C H E D U L E

Dear colleagues,Earlier this year we had the firstmeeting of the Program OrganizingCommittee in Paris. It was verygratifying to see all POC membersassembled together, and I wasimpressed by the collective range of expertise covering allareas in the thyroid field. If we had stayed a few days longer,we could probably have written a new really up-to-datetextbook on thyroidology. I found the meeting veryproductive, as evident e.g. from the detailed information onthe 14th International Thyroid Congress provided in thisfirst announcement: the general outline of the scientificprogram, and the dates of the most important deadlines.What I liked most at our POC meeting, however, was abrain-storming session on how we could improve evenfurther the quality of the congress, and some very good ideasemerged. We keep you informed!I was equally impressed by the expertise of the ProfessionalCongress Organizer in Paris, MCI. They really know theirbusiness, and I would say we all are very fortunate that thelocal organizers Martin Schlumberger and Jacques Orgiazziselected MCI. The congress venue, le Palais des Congrès, hasall necessary amenities, it is easily accessible and beautifullylocated a couple of hundred yards from the Arc de Triomphe.If you like French cuisine, the neighbourhood is abundantwith typical French restaurants and we already had thepleasure to become acquainted with some of them. The socialprogram will boast some unique events, to be disclosed later.I stayed one day more in Paris with my wife, and we fell againin love with Paris in springtime. But Paris is a city for allseasons - so mark the dates in your calendar and plan tosubmit your finest research for presentation at the 14th ITC inParis september 2010.

Wilmar M.WiersingaChairman POC

LOCALORGANISINGCOMMITTEE

President

Martin SchlumbergerVillejuif, France

Vice-President

Jacques OrgiazziPierre Bénite, France

PROGRAMMEORGANISINGCOMMITTEE

Chairman

Wilmar WiersingaAmsterdam, The Netherlands

Members

Marcos AbalovichBuenos Aires, Argentina

Antonio BiancoBoston, USA

Denise CarvalhoRio de Janeiro, Brazil

Sabine CostagliolaBrussels, Belgium

Josef KöhrleBerlin, Germany

Jacques Orgiazzi Pierre Bénite, France

Teofilo O.L. San LuisManila, Philippines

Martin SchlumbergerVillejuif, France

Steven ShermanHouston, USA

Young Kee ShongSeoul, Korea

Yaron TomerCincinnati, USA

Laura Ward Sao Paolo, Brazil

Shunichi Yamashita Nagasaki, Japan

7:00 am

–

8:00 am

–

9:00 am

–

10:00 am

–

11:00 am

–

12:00 am

–

1:00 pm

–

2:00 pm

–

3:00 pm

–

4:00 pm

–

5:00 pm

–

6:00 pm

–

7:00 pm

–

8:00 pm

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM SYMPOSIA

SATELLITESYMPOSIUM

SYMPOSIA

SATELLITESYMPOSIUM

BUSINESS MEETINGS

SATELLITESYMPOSIUM

SYMPOSIA

SATELLITESYMPOSIUMOPENING

CEREMONY

WELCOME COCKTAIL

FACULTY DINNER

CONCERTCONGRESS

DINNER

COFFEE BREAK

COFFEE BREAK

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

SATELLITESYMPOSIUM

LECTUREETA PRIZELECTURE

LATS PRIZELECTURE

ATA PRIZELECTURE

AOTA PRIZELECTURE

ORALCOMMUNICATION

ORALCOMMUNICATION

ORALCOMMUNICATION

ORALCOMMUNICATION

SYMPOSIA

CLOSINGCEREMONYSYMPOSIA

POSTERVIEWIENG

MEET THEEXPERT

SYMPOSIA

POSTERVIEWIENG

MEET THEEXPERT

SYMPOSIA

POSTERVIEWIENG

MEET THEEXPERT

SYMPOSIA

POSTERVIEWIENG

MEET THEEXPERT

POSTER DISCUSSION POSTER DISCUSSION POSTER DISCUSSION POSTER DISCUSSION

ORALCOMMUNICATION

ORALCOMMUNICATION

ORALCOMMUNICATION

ORALCOMMUNICATION

SATURDAY11 SEPTEMBER 2010

SUNDAY12 SEPTEMBER 2010

MONDAY13 SEPTEMBER 2010

TUESDAY14 SEPTEMBER 2010

WEDNESDAY15 SEPTEMBER 2010

THURSDAY16 SEPTEMBER 2010

BREAK

■ Second announcement & call for abstracts: November 2009

■ Deadline for abstracts submission: 30 April 2010

■ Deadline for early bird registration: 30 June 2010

IMPORTANT DATES

annonce1 12/08/08 12:18 Page 2

Absence of survival benefit of radioactive iodine (RAI) after thyroidectomy in low risk differentiated thyroid cancer (DTC) patients.

C. Schvartz 1, F. Bonnetain 2, M. Gauthier 2, A. Cueff 2, S. Fieffe 1, E. Crevisy 3, I. Dygai-Cochet 3, J.-M. Pochart 1, M. Toubeau 3,*

1Endorinology-Nuclear Medicine, Institut Jean Godinot, Reims, 2Statistics and Epidemiology, 3

Nuclear Medicine, Centre Georges Francois Leclerc, Dijon, France

Abstract: Background: After thyroidectomy, the goal of the first dose of RAI is remnant ablation to facilitate the initial staging with the post-therapy scan and to facilitate the early detection of reccurences. Many studies do not show any benefits from RAI for DTC patients at low-risk. Due to conflicting data concerning the risk of recurrences, the ATA and ETA guidelines cannot recommend for or against RAI ablation for this entire subgroup.

Aim: to assess survival benefit of RAI in low-risk thyroid cancer patients

Methods: Using Cancer thyroid registry of Marne Ardennes (1041 pts) and hospital data base of centre Leclerc (257 pts), we included all DTC patients at low risk (age>18 years, multifocal Tp1<1cm, Tp1>1cm, Tp2, all N0 Nx M0, no aggressive histology) from 1975 to 2005. Relevant clinical data were collected : age, sex, surgery modality, RAI intake, tumor size, TNM, histology and survival status. Using univariate and multivariate logistic regressions, we selected relevant variables to explain the trend observed with RAI intake (probability to receive RAI). Then we compared overall survival (OS) -diagnostic date to all deaths- and Disease Free Survival (DFS) -diagnostic date to recurrence, 2nd

Results: Median follow-up was 10.3 years, during which 19 recurrences, 61 other malignant diseases and 105 deaths were registered. 387 patients (30%) received no RAI and 911 had RAI (70%). Univariate logistic regression showed that RAI intake was significantly associated with age (>45 years vs <=45 years OR = 4.2 [3.2-5.4]), sex (female vs male OR = 0.8 [0.5-1.1]), period (>1998 vs <=1998 OR = 1.4 [1.1-1.8]), surgery (thyroidectomy vs lobectomy p<0.0001), histology (vesicular vs papillar OR = 0.49 [0.38-0.64]), Tp (Tp2 vs Tp1 OR = 1.45 [1.13-1.86]), Np (Nx vs N0 OR = 0.33 [0.26-0.43]). In multivariate analysis all these variables were included and retained for propensity score and internally validated by bootstrapping. OS at 10 years was respectively 95.8% and 94.6% for no RAI and RAI group (RAI vs no RAI HR = 1.9 [1.2 – 3.1] et Log-rank p =0.006). DFS at 10 years was respectively 93.1% and 88.7% for no RAI and RAI group (RAI vs no RAI HR = 1.9 [1.3-2.7]et Log-rank p =0.001). After stratification on propensity score, OS at 10 years was respectively 98.4% and 99.2% for no RAI and RAI group (RAI vs no RAI HR = 0.7 [0.4-1.3] et Log-rank p =0.241). DFS survival at 10 years was respectively 97.6% and 96.8% for no RAI and RAI group (RAI vs no RAI HR = 0.8 [0.5-1.3] et Log-rank p =0.313).Multivariate Cox analysis showed that OS was significantly associated with age (>45 years vs <=45 years HR = 7.8 [4.5-13.5]) and sex (female vs male HR = 0.4 [0.3-0.7]) but not with RAI intake (p=0.218). DFS was also significantly associated with age (>45 years vs <=45 years HR = 4.9 [3.3-7.4]) and sex (female vs male HR = 0.6 [0.4-0.9]) and not with RAI (p=0.212). These models were internally validated by bootstrapping.

cancer or all deaths- according to RAI intake with log-rank test and univariate Cox stratified on propensity score. Finally we confirmed these results by computing multivariate Cox model and internally validate it by bootstrapping (1500 replications)

Conclusion: If we confirmed that some clinical characteristics were associated with RAI intake, we failed to demonstrate any survival benefit of RAI in low risk DTC patients.

Disclosure of Interest: None Declared

Keywords: follow-up, thyroid cancer, I-131, ablation, treatment

Analysis of influence of dosimetric factors on the outcome of 131I therapy in patients with hyperthyroidism

M. Knapska-Kucharska 1, L. Oszukowska 1, J. Makarewicz 1, A. Lewinski 2,*

1Department of Nuclear Medicine and Oncological Endocrinology, Province Hospital, Zgierz, 2

Chair and Department of Endocrinology and Metabolic Diseases, Medical University, Lodz, Poland

Abstract: Introduction:

The influence of dosimetric factors on the outcome of 131I therapy has been examined in hyperthyroid patients submitted to 131I treatment. The following factors - which could have influence on the effects of therapy with radioiodine - were analysed: the goitre volume (V), thyroid radioiodine uptake after 24 h (TUP24), effective half-life time of 131

Patients and methods:

I in the thyroid (EHL) and the absorbed dose (D).

Five hundred (500) randomly selected patients with hyperthyroidism, treated with 131I, were studied. They were divided into three groups (based on clinical examination, hormonal and immunological tests, thyroid scintigraphy and ultrasound (US) imaging): Group 1 – patients with multinodular goitre (MNG) (n = 200; 171 females, age 34-81 years; 29 males, age 45-79 years), Group 2 – patients with a single autonomously functioning thyroid nodule (AFTN) (n = 100; 88 females, age 32-79 years;12 males, age 36-70 years), Group 3 – patients with Graves’ disease (GD) (n = 200; 151 females, age 24-81 years; 43 males, age 31-77 years). TUP24 was measured 24 h after oral administration of 3.7MBq 131I, the thyroid or nodule size was measured by US and the volume (V) calculated according to Brunn’s formula, EHL was calculated from thyroid radioiodine uptake measurements between day 1 and 3-6, after the test dose administration. The absorbed dose was calculated according to Marinelli formula, based on the measurements obtained after the test dose administration. In the studied groups, the effects of V, TUP24, EHL and D on the treatment outcome (determined 6 months after 131

Results:

I therapy) were analysed, separately for each group. Regression analysis was used to identify factors affecting therapy results, which were classified as hypothyroidism and euthyroidism (effective therapy), as well as hyperthyroidism (ineffective therapy).

Median TUP24 did not differ between different therapy results in none of study groups. Data regarding V, EHL and D are presented in Table.

Group Treatment outcome Euthyroidism Hyperthyroidism Hypothyroidism

MNG

euthyroid 112 pts, hyperthyroid 50 pts, hypothyroid 38 pts

Median volume [ml]

50** 60*** 32***

Median EHL [days]

6.0 6.0 5.8

Median D [Gy]

156.8 37.5** 191.5**

AFTN

euthyroid 73 pts, hyperthyroid 18 pts,

hypothyroid 9 pts

Median volume [ml]

17** 40,5*** 10***

Median EHL [days]

6.2* 4.9* 4.8

Median D [Gy]

287* 195** 294*

GD

euthyroid 55 pts, hyperthyroid 80 pts, hypothyroid 65 pts

Median volume [ml]

30** 51*** 28***

Median EHL [days]

5.8 5.5 4.4

Median D [Gy]

179 144** 181.5**

*p<0.05; **p<0.01, ***p<0.001

Conclusions

1. The effectiveness of 131

2. We have failed to determine the borderline D, distinguishing between effective and ineffective therapy. The treatment outcome can be predicted with appoximately 70% accuracy, based on minimal absorbed dose.

I therapy depends on the thyroid volume and absorbed dose in all the groups of patients and on the thyroid radioiodine uptake and EHL - in patients with AFTN.

Disclosure of Interest: None Declared

Keywords: hyperthyroidism, radioiodine, treatment

Combined effect of the environmental factors as ionizing radiation and a chronic iodine deficiency on the thyroid gland and the immune condition L. Danyarova 1,* 1

Department of Endocrynology, RESEARCH INST.OF CARDIOLOGY AND INTERNAL MEDICINE, Almaty, Kazakhstan

Abstract: The tragic situation of Semipalatinsk nuclear range is an acute and chronic radiation, repeated in big and small doses and a total absence of territorial deactivation, created unique conditions for study of the long term influence of the radiation doses on the health of the population. The Semipalatinsk region of the Republic of Kazakhstan belongs to area of moderate and pronounced iodine deficiency. Physiological strain of a thyroid gland in the conditions of such aggressive environmental factors, such as ionizing radiation and a chronic iodine deficiency results in deregulation of immune and endocrine systems. The purpose of the research is to study the prevalence of a thyroid gland pathology and the condition of a cytokine immune link of those who is influenced by a combine effect of ionizing radiation and a chronic iodine deficiency. Prospectively, 1100 people passed through the investigation, 20,5% of them has shown the possibility of thyroid gland good quality formations occurrence, 0,9% - thyroid gland cancer, 19,2% - autoimmune thyroiditis, 14,7% - diffuse goiter, 1,45% - toxic goiter. Thus, 56,75% had a thyroid pathology. Thyroid gland functional condition analysis (TSH, FT3, FT4 a-TG, a-TPO) has shown the prevalence of a subclinical hypothyroidism (33%). 28,8% resulted in the presence of antibodies to thymoglobulin and the thyroid peroxides, whereas in the areas located further to the nuclear range, the percentage was only 13,0%. The research has identified the misbalance in subpopulation of the Th-1 and Th-2 cells, accompanied by the oppression of the humoral immune link: excessive content of IL-1β and TNF-α low-range content of IL-2. The activation of T-cells results in occurrence of a large quantity of the receptor for IL-2 (DC-25) on the surface. The special features of the immune system cells misbalance, exposed among those who suffers from thyroid pathology, contribute to the understanding of the processes of the environmental factors influence, such as such as ionizing radiation and a chronic iodine deficiency. And it also allows to forecast the occurrence of autoimmune pathological processes. Disclosure of Interest: None Declared Keywords: iodine deficiency, low dose of radiation, thyroid gland

Comparison of four strategies of radioiodine ablation in patients with thyroid cancer with low-risk of recurrence: the randomized, prospective ESTIMABL study on 753 patients

B. Catargi 1,*, I. Borget 2, D. Deandreis 3, S. Zerdoud 4, B. Bridji 5, S. Bardet 6, A. Rousseau 7, D. Bastie 8, C. Schvartz 9, P. Vera 10, O. Morel 11, D. Benisvy 12, C. Bournaud 13, F. Bonichon 14, C. Dejax 15, M.-E. Toubert 16, E. Benhamou 2, M. Schlumberger 3

1Endocrinology Department, CHU Bordeaux , Bordeaux , 2Biostatistic and Epidemiology Service , 3Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy , Villejuif, 4Nuclear Medicine Department , Institut Claudius Regaud, Toulouse, 5Nuclear Medicine Department , Centre René Gauducheau , Saint-Herblain, 6Nuclear Medicine Department , Centre François Baclesse, Caen, 7Nuclear Medicine Department, Pitie-Salpetriere, Paris, 8Endocrinology Department, CHU Toulouse, Toulouse, 9Nuclear Medicine Department, Centre Jean Godinot, Reims, 10Nuclear Medicine Department, Centre Henri Becquerel , Rouen , 11Nuclear Medicine Department, Centre Paul Papin, Angers, 12Nuclear Medicine Department, Centre Lacassagne, Nice, 13Nuclear Medicine Department, CHU Lyon, Lyon, 14Nuclear Medicine Department, Institut Bergonie, Bordeaux , 15Nuclear Medicine Department, Centre Jean Perrin, Clermont-Ferrand, 16

Nuclear Medicine Department, Hopital Saint-Louis, Paris, France

Abstract: Purpose:

The objective of this clinical trial is to compare four strategies of management of postoperative radioiodine ablation in a 2x2 factorial design, each strategy combining a method of TSH stimulation and an activity of 131I. The primary endpoint is the rate of thyroid ablation.

Patients and Methods

This multicentric, randomized, controlled, phase III trial involved 24 French centers, and compared 4 strategies for postoperative radioiodine ablation in a 2*2 factorial design: a method of TSH stimulation (either thyroid hormone withdrawal (THW) or rhTSH (Thyrogen®, Genzyme)) and an activity of 131I (either 1.1 GBq or 3.7GBq). Study patients met the following criteria: age>18 yrs; total thyroidectomy for differentiated papillary or follicular (no aggressive histology) thyroid carcinoma, between 30 and 120 days before randomization, treatment with LT4 for at least one month; TNM stage pT1<1cm, N1 or Nx, pT1>1cm (any N) or pT2, N0; absence of distant metastasis, no iodine contamination. Thyroid ablation was assessed at 6-10 months after radioiodine ablation with rhTSH stimulated Tg determination and neck-US; whole-body scan was performed in case of positive Tg antibodies (TgAb). The comparison between the four strategies is based on equivalence framework, with two-side α=0.05.

Results

753 patients who gave written informed consent were included in the study between April 2007 and February 2010 and currently data on radioiodine ablation are available for 693 patients (92%) who form the basis of the present report: 79% were females, mean age was 49 years, and 90% had papillary cancer; 30% of tumors were pT1N0, 17% were pT1N1, 39% were pT1,Nx and 12% were pT2,N0. Mean time between thyroidectomy and randomization was 50 days, and mean time between randomization and radio-iodine ablation was 39 days.

Data on the follow-up control are currently available for 477 patients. Neck-US was normal in 444 patients (93%) and suspicious or abnormal in 33 (7%). Stimulated Tg level was >1.0 ng/mL in 25 (5%) patients and 31 patients had TgAb. Thyroid ablation was considered complete in 417 patients (87%), incomplete or doubtful in 58 patients (12%) and non-evaluable in 2 patients.

Conclusion:

These data will be updated for the ITC meeting, and results of ablation will be presented for more than 600 patients according to the treatment group.

Disclosure of Interest: None Declared

Detection of increased frequency of thyroid hypoplasia in subjects irradiated in utero as the result of Chernobyl catastrophe.

V. Drozd 1,*, L. Danilova 1, M. Lushchyk 1, T. Leonova 1, T. Platonova 1, A. Grigorovich 2, V. Sivuda 2, I. Branovan 3, I. Biko

4, C. Reiners 4

1International Fund "Arnica", Minsk, 2Brest Regional Endocrinological Dispensary, Brest, Belarus, 3Chernobyl Project, New-York, United States, 4

Clinic and Policlinic of Nuclear Medicine, University of Würzburg, Würzburg, Germany

Abstract: For the 24 years passed after the Chernobyl catastrophe a significant experience in estimation of medical consequences of thyroid irradiation among Belarusian patients had been accumulated. Estimation of official statistical data, performance of screening and special epidemiological research allowed to prove a sharp increase of incidence of radiation induced cancer in Belarus. By the results of different projects, realized in contaminated areas of Belarus (programs of the Belarusian Institute of Radiation Medicine, IAEA, WHO, Sasakawa-Fund, Belarusian-American Project, Red Cross Federation, Fund Arnica, Chernobyl Project), in the period of 1990-2010 years carcinomas were revealed among children and adolescents with the frequency from 0,11% to 0,62%. Currently, there is an alarming fact of not only growing incidence of thyroid cancer among the adults, but also an increase in acquired hypothyroidism incidence in Belarusian population. By official statistical data, morbidity rate of acquired hypothyroidism was 1.9/100 000 of children in 1993, and in 2008 it increased up to 20.8/100 000. Among the adults, this parameter was 11.7/100 000 in 1998 and increased to 37.9/100 000 in the year 2008. Previously, data were published that the massive emission of 131

The aim of our screening ultrasonic examination was the detection of the thyroid hypoplasia prevalence in the regions affected with the radionuclide fallouts.

I from Hanford nuclear facility in USA (1945) appeared to be associated with the subsequent occurrence of epidemic juvenile hypothyroidism among children living downwind.

Since 2004 to 2007 thyroid ultrasound with volume estimation was performed in 3311 Belarusian subjects, living on the areas of Brest region with the different contamination rate density. Examined subjects were divided in 3 groups: 1– irradiated at the age of 1 to 3 years old at the moment of ChNPP catastrophe, 2 – irradiated in utero, 3 – born after the catastrophe.

It was revealed that thyroid hypoplasia was detected in 3% of group 1 (out of 1876 persons), in 5,8% of group 2 (out of 503 persons, P<0.05) and in 1,7% of the third group (out of 932 persons). Separating of the irradiated in utero subjects (group 2) to subgroups in dependence of the gestation period, showed the highest prevalence of thyroid hypoplasia among the irradiated in the first trimester of gestation -7,7% (P<0.05), in the second trimester - 5,3%, in the third trimester - 4,7%.

Out of entire cohort 446 patients were selected, who lived on the most contaminated areas of Stolin district. They were also separated to 3 groups in accordance to their age at the moment of irradiation as the main cohort. Prevalence of thyroid hypoplasia formed 2,7% in the 1-st group (out of 110 patients), 7,1 % in the second (out of 99 patients, P<0.05) and 0,4% in the 3-rd (out of 237 patients). Among the in utero irradiated: 1-st trimester –10,3%, (P<0.05) second – 4,3% and third – 5,4%.

So, our data reveal an increased risk of thyroid hypoplasia development in subjects irradiated in utero, especially at the 1-st trimester of gestation (P<0.05). The more thorough screening studies are still required to prove that radiation exposure “in utero” can lead to a significant increase of thyroid hypoplasia and to find the reasons of an increase in acquired hypothyroidism incidence.

Disclosure of Interest: None Declared

Keywords: HYPOPLASIA, HYPOTHYROIDISM, RADIATION-ASSOCIATED THYROID DISEASES

Distinctive Genomic Profiles of Normal and Transformed Thyrocytes Irradiated with Low vs. High Doses of X-irradiation both in vitro and in vivo K. Abou-El-Ardat 1, 2,*, P. Monsieurs 3, A. Janssen 1, M. Beck 1, A. Michaux 1, N. Anastasov 4, M. Atkinson 4, R. Benotmane 1, H. Derradji 1, S. Bekaert 2, W. Van Criekinge 2, S. Baatout 1 1Radiobiology, SCK-CEN, Mol, 2Molecular Biotechnology, Universiteit Gent, Ghent, 3Microbiology, SCK-CEN, Mol, Belgium, 4

Radiobiology, Helmholtz Zentrum München, Munich, Germany

Abstract: The increase in cases of papillary thyroid carcinoma (PTC) in the aftermath of the Chernobyl disaster led to an elevation of interest in the effect of radiation on the thyroid. A lot of research has focused on the effect of high doses of radiation on the thyroid, however, debate still rages on the effect of low doses on various organs including the thyroid. Our work hopes to uncover some of the effects of low doses of external X-radiation in in vitro and in vivo models using several techniques and robust analysis. Here we describe the use of such models combined with microarrays and sound statistical analysis. Previous work done by us on a cell line, TPC-1, of papillary thyroid carcinoma with a RET/PTC1 translocation, showed that radiation, even at low doses, caused a halt in proliferation, an activation of the G1/S and G2/M checkpoint and a senescent phenotype. In addition, our results revealed that the cell line retained a functional copy of the tumor suppressor p53. We subsequently extracted total mRNA from the cells and using Affymetrix chips for human cells, studied the genome-wide response of these cells to low (0.0625 Gy), medium (0.5 Gy) and high (4 Gy) doses of X-rays. In addition, we subjected a strain of C57BL mice with a RET/PTC translocation to the same doses of X-rays and compared them to the same strain with no translocation. 83 genes were commonly regulated between RET/PTC-positive and –negative cells upon irradiation and 14 genes were differentially regulated, among which are apolipoprotein E (ApoE) and type I deiodinase (D1). Fourteen genes were common between the human cell line, TPC-1 and the mice with RET/PTC translocation with three genes differently regulated between the two upon a 4 Gy dose of radiation. A low dose of X-rays (62.5 mGy) did not cause a large change in RET/PTC-positive mice and TPC-1 cells, with only 59 genes and 18 genes regulated respectively while the same dose caused a grand number of 2300 genes to be altered in wild-type mice. Among the pathways regulated in wild-type mice and absent in RET/PTC-positive is the thyroid hormone synthesis pathway which was up-regulated. In addition, all radiation doses caused an up-regulation of the sodium coupled monocarboxylate transporter (SMCT) with reported tumor suppressor activity, slc5A8, in wild-type mice. Furthermore, we used the same RNA from TPC-1 cells and using high-throughput RT-PCR, we evaluated the response of some 380 microRNAs (miRNA) to the same doses of irradiation. We then searched for the known targets of the significantly regulated miRNAs within the list of genes from the microarray experiment and drew a correlation between the regulation of miRNAs and genes. In conclusion, we find that low doses of radiation act differently on murine thyroids carrying and lacking the RET/PTC translocation and even bear a distinctive profile to higher irradiation doses in both in vitro and in vivo models. We also find that miRNAs are involved in the response of these cells to radiation, even at low doses and that two in particular, let-7g and miR-106a, were significantly involved in the cells' p53-mediated anti-proliferative response. This work is financially supported by the EU Euratom programme (GENRISK-T contract FP6-36495). Disclosure of Interest: None Declared Keywords: Papillary thyroid carcinoma, RET/PTC rearrangements, X-rays

DUOX 1 is induced in human thyroid cells submitted to X-Ray irradiation and is responsible for the bystander effect M. Boufraqech 1,*, R. Ameziane el hassani 2, O. Chevallier Lagente 1, U. weyemi 1, M. Talbot 1, A. Al Ghuzlan 1, F. courtin 1, J. M. bidart 1, M. Schlumberger 1, C. dupuy 1 1UMR 8200 CNRS, INSTITUT GUSTAVE ROUSSY, Villejuif, France, 2

UBRM., UBRM, Centre National de l’Energie, des Sciences et des Techniques Nucléaires, , Rabat, Morocco

Abstract: * M. Boufraqech and R. Ameziane El Hassani contributed equally to this work. Introduction: Radiation-induced bystander effect is the mechanism by which cells that have not been directly exposed to ionizing radiation behave like exposed cells: they die or show chromosomal instability and other phenotypic abnormalities. Bystander cells may be either adjacent or at some distance from the exposed cells. Irradiated cells release soluble factors that can be transferred through cell culture medium to non-irradiated cells. These factors include cytokines and reactive oxygen species (ROS). The aim of this study was to identify the ROS generating system induced by X-ray irradiation of human thyroid cells that could be responsible for the bystander effect. Methods: Human thyroid epithelial cells (HTori-3) were irradiated with doses of 2, 5, or 10 Gy X-ray using an X-ray generator operating at 200 KVe, 15 mA, and 1 Gy/min. Extracellular production of H2O2 was assessed by reaction with cell-impermeable Amplex Red reagent in the presence of excess peroxidase producing fluorescent resorufin. Q-PCR was performed on the equivalent of 10 ng total RNA per tube. Oligonucleotide primers and Taqman probes specific for DUOX1, DUOX2, NOX4, DUOXA1 and DUOXA2 were designed to be intron spanning (Applied Biosystems). Results: Irradiation of HTori-3 cells induced an extracellular production of H2O2 after 4 days that was related to the radiation dose. Time course analysis of H2O2 production in response to 10 Gy showed an increase within 2-4 days that reached a plateau level within 4-15 days. Because NADPH oxidase inhibitors (that inhibit NOX and DUOX activity) decreased the bystander effect, we analyzed the effect of radiation on NOX and DUOX mRNA expression levels, and only DUOX1 mRNA was found to be induced by radiation exposure. Also, the mRNA of DUOXA1, the maturation factor of DUOX1 was induced by irradiation. These results were confirmed by western blot analysis. Knocking down DUOX1 with specific siRNA reduced radiation-induced H2O2 formation, indicating that X-ray irradiation induced extracellular H2O2 production via DUOX1 up-regulation. Irradiation of human thyrocytes and primary human fibroblasts produced the same effect. Conclusions: Radiation exposure increases DUOX1 expression after several days, suggesting that this H2O2 generating system could be responsible for the late bystander effect. This could have a potential importance for radiation risk assessment and for cancer radiotherapy. Disclosure of Interest: None Declared Keywords: bystander effect, DUOX 1, Irradiation

Genome-wide gene expression induced by ionizing radiation and hydrogen peroxide in human thyroid primary cultures and T-cells. S. Versteyhe 1,*, N. Driessens 1, M. Tarabichi 1, J. E. Dumont 1, F. Miot 1, B. Corvilain 1, V. Detours 1 1

IRIBHM, ULB, Brussels, Belgium

Abstract: Ionizing radiation is an established cause of thyroid cancer and growing evidence supports a role for H2O2 (hydrogen peroxide) in spontaneous thyroid carcinogenesis. The molecular programs activated by these two agents in the thyroid are not fully understood. We have profiled genome-wide gene expression induced by low dose γ-radiation and H2O2

Human thyroid primary cultures were prepared from the healthy thyroid tissue of 8 patients operated for non-cancerous thyroid pathologies. T-cells were isolated from the blood of the same patients. The thyroid cells and the T-cells of each patient were either 1) left untreated, 2) treated with 1 Gy γ-radiation or 3) treated with H

in primary human thyroid cells, and also in T-cells in order to gain insight into cell type-specific effects.

2O2. Two H2O2 doses were determined using alkaline COMET and H2

As measured by alkaline COMET assay, 50 and 10 microM H

AX phosphorylation assays, as to elicit levels of DNA single- and double-strand breaks equivalent to 1 Gy γ-radiation. Gene expression was profiled in the two cell types in all four conditions, four hours after treatment, using full genome Affymetrix U133+v2 microarrays.

2O2 induced a similar level of DNA single- and double-strand breaks as 1 Gy of γ-radiation in thyroid cells and T-cells respectively. Similarly, measuring phosphorylated Ser139 histone H2AX levels revealed that 200 and 70 microM H2O2 induced a similar level of DNA double-strand breaks as 1 Gy γ-radiation in thyroid cells and T-cells respectively. Thus, H2O2 inflicts more damage to T-cells than to thyroid cells. One Gy γ-radiation induced subtle transcriptional responses, i.e. small compared to the expression variation observed between cell type-matched untreated controls from different individuals. Yet, the γ-radiation responses of T-cells and thyroid cells were remarkably similar, with a strong over-representation of DNA damage repair and apoptosis genes. The highest H2O2 dose exhibited a cell type-specific effect, with more genes regulated in T-cells than thyroid cells. By contrast, no genes were found to be regulated in any cell type at the lowest H2O2

While γ-radiation causes similar amounts of DNA damage and similar transcriptional responses in T-cells and thyroid cells, H

dose using standard gene-wise statistical procedures for the detection of differentially expressed genes.

2O2

incurs less damage and a weaker transcriptional response in thyroid cells than in T-cells, suggesting that thyroid-specific protective mechanisms may be at work. These expression data will be instrumental in interpreting in vivo transcriptional profiles from post-Chernobyl studies such as the GENRISK-T study.

Disclosure of Interest: None Declared Keywords: hydrogen peroxide, microarray gene expression profiling, radiation

Global micro RNA expression in papillary thyroid carcinomas of young patients exposed to radiation

K. Unger 1,*, A. Elmahjoub 1, T. Bogdanova 2, G. Thomas 1

1Human Cancer Studies Group, Surgery and Cancer, IMPERIAL COLLEGE LONDON, London, United Kingdom, 2

Institute of Endocrinology and Metabolism, Academy of Medical Sciences of the Ukraine, Kiev, Ukraine

Abstract: One of the main effects of the Chernobyl reactor accident is an increase in childhood papillary thyroid carcinomas (PTC) in the regions that were contaminated with radio-iodine from the fallout. Despite a considerable research effort, molecular profiles have yet to be identified that reliably distinguish between age matched patients with radiation associated and sporadic PTCs. Expression of micro RNAs (miRNA) have recently been studied extensively in many different cancer types. MiRNAs have the potential to provide insights into the network of molecular pathways that are involved in the development of tumourigenesis as they are involved in the regulation of networks of mRNAs. In addition, miRNAs can be studied in formalin-fixed paraffin embedded material, making them ideal for clinical studies.

This study was designed specifically to identify differentially expressed miRNAs in patients with childhood PTC that were exposed (n=11) and non-exposed (n=9) to irradiation. MiRNA enriched total RNA was extracted from sections of formalin-fixed paraffin embedded tumour tissues which were obtained from the Chernobyl Tissue Bank (CTB). The miRNA was fluorescently labelled and hybridised to miRNA arrays (Agilent Human Microarray v3) which contain probes for 866 human miRNAs. The raw fluorescence intensities were normalised using vsn (variance stabilisation normalisation) and the linear-model fitted data were tested for differential expression of miRNAs in the exposed and the unexposed group. The list of significantly (p<0.05, not FDR controlled) differentially expressed miRNAs was translated into a list of predicted target genes which were subsequently tested for enrichment of Gene Ontology (GO) terms and pathways (KEGG) using hypergeometric testing (FDR < 0.05, R package CORNA).

Our results showed that miRNAs miR-193b, miR-720, miR-1274 and miR-933 were specifically down-regulated and that miR-513b, miR-513c, miR-513a-5p, miR-1246, and miR-489 were specifically up-regulated in the exposed group. GO term enrichment analysis showed that GO terms (Molecular Function and Biological Process) that are related to DNA binding were enriched. Moreover pathway enrichment analysis showed enrichment of genes that are part of the Fc epsilonRI signalling and VEGF pathway (both linked to the MAP kinase pathway) and the p53 signalling pathway.

The results suggest that in radiation-associated childhood PTC DNA repair processes which are reflected by genes that encode DNA-binding proteins are deregulated. DNA mutation and double-strand breaks are induced by ionising radiation and subsequent misrepair and inactivation of tumour suppressor genes and the activation of oncogenes leads to growth and proliferation of the tumour cell. These findings suggest that In addition to the MAP kinase pathway which is known to be a key pathway in PTC, additional pathways such as the Fc epsilon RI signalling, the VEGF pathway and p53 signalling pathway seem to be involved in radiation-associated tumourigenesis of PTC.

These data are currently being validated in a larger series of cases that are ag-e and residency-matched but differ in exposure to radioiodine in fallout from the Chernobyl accident.

Disclosure of Interest: None Declared

Keywords: expression, miRNA expression, Papillary thyroid carcinoma

HiLo: Multicentre randomised phase III clinical trial of high vs low dose radioiodine, with or without recombinant human thyroid stimulating hormone (rhTSH), for remnant ablation for differentiated thyroid cancer

U. Mallick 1,* and C Harmer, S Clarke, L Moss, A Nicol, P Clarke, J Smellie, R McCready, K Farnell, J Franklyn, R John, C Nutting, B Yap, C Lemon, J Wadlsey, G Gerrard, T Roques, E Macias, S Whitaker, A Abdul-Hamid, P Alvarez, L Kadalayil, A Hackshaw

1

FREEMAN HOSPITAL, NEWCASTLE, Newcastle upon Tyne, United Kingdom

Abstract: Background

Recommended treatment for most patients with differentiated thyroid cancer is surgery followed by radioiodine ablation. Current practice in many centres is to use a high administered activity of 3.7 GBq (100mCi). However, a lower activity (1.1 GBq or 30 mCi) has advantages including a shorter stay in hospital isolation and lower risk of side effects, including the risk of a second cancer. Also, Thyrogen (rhTSH) allows patients to continue thyroid hormone replacement during ablation, avoiding symptoms of hypothyroidism and also reduces total body radiation dose. A systematic review could not reliably determine whether a lower activity has a similar effect as 3.7 GBq, or whether concomitant use of Thyrogen reduces ablation success rates, because there have only been small studies. We conducted a large randomised factorial multicentre trial to simultaneously address whether ablation success rates are similar using (i) either 1.1 GBq or 3.7 GBq, and (ii) either Thyrogen or thyroid hormone withdrawal. It is the first ever national prospective trial in thyroid cancer in the UK.

Methods

Patients were eligible if: tumour stage pT1-T3, and NX, N0 or N1, M0 (TNM 6th edition); they had undergone a total thyroidectomy by a specialist surgeon (R0 resection), with or without lymph node dissection. Patients were randomised to one of four arms: 1.1 or 3.7 GBq, each with Thyrogen (given on each of the two days before ablation) or thyroid hormone withdrawal. All patients were put on a low iodine diet and had a pre-ablation scan using Technetium 99m (to assess remnant size). Ablation success was determined 6-9 months later using an I-131 iodide diagnostic scan (uptake

Results

This preliminary analysis is of 391 patients recruited from 31 UK centres from the National Cancer Research Network; January 2007-April 2010. Median age 44 years; 77% female. Results on ablation success rates and toxicities will be available in September 2010.

Conclusions

Preliminary results will indicate whether 1.1 GBq could be used instead of 3.7 GBq, and whether patients could have Thyrogen to allow them to continue thyroid hormone replacement during ablation. Final results will be available in 2011.

Disclosure of Interest: U. Mallick Consultant for Advisory panel to Genzyme

Keywords: differentiated thyroid cancer, radioiodine ablation, Thyrogen

HISTOLOGICALLY AGGRESSIVE TYPES OF FOLLICULAR CELL-DERIVED THYROID CANCER OFTEN HAVE RADIOACTIVE AVID DISTANT METASTASES: A STUDY OF 314 PATIENTS WITH DISTANT METASTASES AT A SINGLE INSTITUTION.

H. P. Tala 1,*, G. Rondeau 1, R. A. Ghossein 2, J. A. Fagin 1, R. K. Grewal 3, S. M. Larson 3, R. M. Tuttle 1

1Endocrinology division, Department of Medicine, 2Pathology Department, 3

Radiology Department, Nuclear Medicine Division, MEMORIAL SLOAN KETTERING CANCER CENTER, NEW YORK, United States

Abstract: INTRODUCTION: Radioactive iodine (RAI) remains one of the primary treatment options for metastatic, follicular cell derived thyroid cancers. While it is widely accepted that metastatic lesions arising from classical papillary or well-differentiated follicular thyroid cancers are usually RAI avid, whether metastatic lesions arising from more aggressive histologic phenotypes will be RAI avid is much less well understood. The aim of this study was to determine the likelihood that metastatic lesions arising from one of the aggressive thyroid cancer histologies [tall cell variant of papillary thyroid carcinoma (TCV-PTC), poorly differentiated thyroid carcinoma (PDTC) and Hürthle cell carcinoma (HCC)] would demonstrate sufficient RAI avidity for visualization on RAI scanning and therefore could potentially benefit from RAI therapy.

METHODS: This is a single institution, retrospective study of all thyroid cancer patients with distant metastases (documented on cross sectional and/or functional imaging) referred to nuclear medicine for RAI scanning or therapy between January 1998 and March 2010, in whom complete clinical information was available. Patients with second primary malignancies were excluded if distant metastasis (DM) could not be clearly attributed to thyroid cancer. Diagnostic RAI whole body scans (Dx-WBS) and post-therapy RAI whole body scans (Rx-WBS) were analyzed in each patient. Patients were considered to have RAI avid disease if any of the metastatic lesions were visualized on either the Dx-WBS or Rx-WBS. RAI avidity of metastatic lesions was determined for each of the following predominant primary tumor histologic subtypes: well differentiated follicular thyroid carcinoma (WD-FTC), follicular variant of papillary thyroid carcinoma (FV-PTC), classical papillary thyroid carcinoma (C-PTC), TCV-PTC, PDTC and HCC.

RESULTS: Distant metastases were identified in 379 patients on either cross sectional and/or functional imaging and 314 patients met the inclusion criteria. The median age was 59 years (range 6-85), 51% were female and 90% had structural evidence of DM. Distant metastases were present only in the lungs in 57%, only in bone in 19%, in both bone and lungs in 17% and in multiple organs in 7%. Overall 73 % had RAI avid distant metastases visible on RAI scan. The highest rate of RAI avid metastases was seen in the FV-PTC (91%) and in WD-FTC (90%). C-PTC patients demonstrated RAI avid metastatic lesions slightly less often (77%). Surprisingly, the PDTC patients had RAI avid metastatic lesions at a rate similar to the TCV-PTC patients (69% vs 64%, respectively). As expected, HCC patients were much less likely to have RAI avid distant metastases (34%). (See figure).

CONCLUSIONS: In patients selected for RAI scanning or therapy at our center, RAI avid lesions can be identified in more than two thirds of the patients with distant metastases arising in the setting of C-PTC, WD-FTC, FV-PTC, TCV-PTC, or PDTC primary tumors. While RAI avidity on a post-therapy scan does not always correlate with clinically significant tumoricidal activity, it is likely that some of these patients with RAI avid metastatic disease did obtain a clinical benefit.

Image / Graph:

Disclosure of Interest: None Declared

Keywords: distant metastases, RADIOACTIVE IODINE, Thyroid cancer

Low radiation dose to relatives after discharge of thyroid cancer patients treated with I-131

H. Remy 1,* on behalf of PHARMACY, E. CAMPS 1, M. RICARD 2, I. BORGET 3, F. LAVIELLE 2, J. COULOT 2, M. SCHLUMBERGER 4

1PHARMACY, 2MEDICAL PHYSICS, 3HEALTH ECONOMICS, 4

NUCLEAR MEDICINE and UNIVERSITY PARIS-SUD, BICETRE, INSTITUT DE CANCEROLOGIE GUSTAVE ROUSSY, VILLEJUIF, France

Abstract: INTRODUCTION. Patients treated with I-131 for thyroid carcinoma are potential source of radiation exposure for other individuals. To provide more reliable information to patients and relatives, this study evaluated the radiation dose received by family members after discharge from the hospital. Influence of rhTSH stimulation or withdrawal has also been investigated.

MATERIAL AND METHOD. Fifty consecutive thyroid cancer patients have been included in the study after informed consent. Post operatively; all patients received 3.7 GBq of I-131, 20 after rhTSH and 30 after withdrawal. A calibrated NaI (Tl) counting device (ARIES – France) implemented in the treatment room was used to measure whole-body retention during hospitalization (3 days). Dose rate was measured (Ramda-2000 ROTEM – Israel) at 1 meter from the thyroid bed before discharge from the hospital. A total of 76 family members were monitored during 7 days after discharge using an electronic personal dosimeter (Mirion MGP – France). Before discharge, protection rules and a questionnaire on life conditions were given to the patients.

RESULTS AND DISCUSSION. At discharge, respectively for rhTSH and withdrawal patients, the mean residual activity was 112 MBq and 226 MBq (p=0.015), the mean effective half-life 0.53 and 0.64 (p=0.017) and the mean dose rate 2.2 and 5.2 µSv/h (p=0.0001). The mean cumulated radiation dose delivered to the relatives during the 7 days following discharge was similar (p=0.37) with either rhTSH (58 µSv) or withdrawal patients (49.6 µSv). The time spent nearby the patient was longer for rhTSH patients (40.9 h) than for withdrawal patients (30.9 h) (p=0.04). ¾ of the radiation dose is delivered during the first 3 days after discharge. Less than 10 % of the administered activity remained in more than 85 % of cases.

CONCLUSION. Three main observations can be drawn. First, rhTSH stimulation leads to lower irradiation when mean rate is considered (cumulated irradiation divided by time contact) 1.4 µSv per hour compared to 1.6 µSv with withdrawal. However, this had no impact on the radiation dose received by relatives, because of a longer time spent close to the patient when rhTSH is used. Second, most relatives involved in direct care received a whole body exposure of less than 50 mSv that is well below the dose constraints of the ICRP publication n°94 (5 mSv per episode). Third, in euthyroid patients after rhTSH, the whole body retention of I-131 after three days of hospitalization is significantly lower than in hypothyroid patients after withdrawal. The hospital stay can be shortened when rhTSH is used.

Disclosure of Interest: None Declared

Keywords: Thyroid cancer, radiation protection, rhTSH

Nodular goiter after occupational accidental exposure to radiation M. A. Pisarev 1, 2,*, M. Schnitman 3 1Radiobiology, National Atomic Energy Commission , 2Human Biochemistry, University of Buenos Aires School of Medicine, 3

Center of Endocrinology and Metabolism, French Hospital C. Milstein, Buenos Aires, Argentina

Abstract: Introduction: The occurrence of nodular goiter after radiation exposure has been documented. Increased incidence of thyroid nodules and cancer after head and neck irradiation as a treatment of enlarged thymus or tonsils and tenia capitis, Follow-up of survivors from atomic bomb explosions or nuclear accidents indicated the causal relationship between radiation and nodular goiter. A recent review called the attention to the possible generation of autoimmune thyroid disorders under similar circumstances. In the present report we present the consequences of an accidental occupational radiation exposure at a local hospital in Buenos Aires. For obvious reasons the identification of the hospital as well as the identity of the persons involved is not disclosed. Materials and Methods: Control at a local Radiology Service showed the lack of correct shielding in the X-ray equipment. The physicians and technicians exposed to radiation during 12 months were examined (14 persons, 5 males and 9 females, age range 29-54 years).Clinical work-up, included thyroid sonography, assay of total T3, T4,

Conclusions: it may be concluded:

TSH, thyroid antibodies, TRH-TSH tests and fine needle aspiration biopsy of thyroid nodules. Similar studies were performed in a group of unexposed physicians and technicians (8 females and 5 males, age range 27-60 years). Results: The exposed patients had normal values of circulating T3, T4 and TSH, except two of them with increased basal TSH and normal iodothyronines, suggesting subclinical hypothyroidism. One patient had lower T4 and another had an abnormal TRH-TSH test. Sonography demonstrated thyroid nodules in 11 out of the 14 patients, an additional patient had diffuse goiter. Among the 11 with nodular goiter in 5 the follow-up demonstrated nodule growth or the appearance of new nodules. Abnormal spermogram in two out of 5 males (previously fertile). One patient with increased TSH, increased thyroid antibodies were found, while another had an abnormal TRH-TSH test. All non-exposed cohort were normal. No cancer cells were found by FNA.

a) In 11 out of 14 radiation-exposed patients nodular goiter developed and an additional patient had diffuse goiter. Therefore total goiter incidence was 12/14 (85.7%). b) In 5 of the nodular goiter patients an increase in the size or the appearance of new nodules was observed along the follow-up period. No cancer was detected by FNA. c) Hypothyroidism was observed in 3/14 patients, and an additional patient had an abnormal TRH-TSH test, suggesting subclinical hypothyroidism. d) Increased circulating antithyroid antibodies were found in one of the hypothyroid patients. Disclosure of Interest: None Declared Keywords: goiter, radiation, thyroid

Protection Against 131I-induced Double Strand DNA Breaks in Thyroid Cells

J. M. Hershman 1,*, A. Okunyan 1, S. Cannon 1, V. Hogen 1, Y. Rivina 2

1Endocrinology, UCLA-VA, 2

Radiation Biology, UCLA, Los Angeles, United States

Abstract: Background: Radioiodine-131 released from nuclear reactor accidents has dramatically increased the incidence of papillary thyroid cancer in exposed individuals, especially young children. The accepted measure for prevention of radiation-induced thyroid cancer is potassium iodide tablets that contain 100 mg iodide taken daily to block thyroid uptake of the 131

Methods: In order to test the effect of monovalent anions that compete with NIS and to test compounds that protect from or mitigate the effects of radiation, we developed a cell model using rat FRTL-5 cells incubated with

I. The deposition of ionizing radiation in cells results in double-strand DNA breaks (DSB) at fragile sites, and this early event can generate oncogenic rearrangements that eventually cause the cancer.

131

Results: Incubation with 1 to 16 microCi

I. The DSB were measured by nuclear immunofluorescence using antibodies to 53BP1 (p53-binding protein 1) or gammaH2AX (histone H2AX phosphorylated on serine 139).

131I /ml for 90 min resulted in a dose-related increase of DSB that was identified in 75 to 85% of cells at 8 to 16 microCi/ml. 10 microCi 131I/ml for 60-90 min resulted in estimated radiation doses of 1 to 3 Gy. After 60 to 90 min, the number of DSB increased from a baseline of 4-15% before radiation to 65-90% after radiation. GH3 or CHO cells that do not transport iodide did not develop DSB when incubated with 10 microCi 131I/ml for 90 min. Incubation with 20-100 microM iodide or thiocyanate markedly attenuated DSB. Perchlorate was about 5 times more potent than iodide or thiocyanate, causing significant reduction of DSB at 4 to 10 microM ClO4-. The effects of the anions were much greater when each was added 30 to 60 min before the 131I and were reduced when added 30 to 60 min after the 131I. Two organic compounds recently shown to provide radiation protection partially prevented DSB caused by 131

Conclusion: We have developed a thyroid cell model to quantify the mitogenic effect of

I and had additive effects with perchlorate.

131I. 131I causes double strand DNA breaks in FRTL-5 cells detected by 53BP1 or gammaH2AX and had no effect on cells that do not transport iodide. Perchlorate, iodide, and thiocyanate protect against DSB induced by 131I. Preincubation with the anion or radioprotective compounds prevents DSB; delayed addition of the anion is much less effective. These data provide a basis for studies of radioprotection against DSB induced by 131

I in animals in order to refine the prevention of thyroid cancer resulting from nuclear fallout.

Disclosure of Interest: None Declared

Keywords: Double strand DNA breaks, iodine-131, perchlorate

Radiation-induced thyroid cancer after radiotherapy for childhood cancer . M. Jiravová 1,* 1

Department of Nuclear Medicine and Endocrinology, FACULTY HOSPITAL MOTOL, UK ,PRAGUE, CZECH REPUBLIC, Prague, Czech Republic

Abstract: Radiation - induced thyroid cancer after radiotherapy for childhood cancer. Mária Jiravová M.D, Petr Vlček M.D. Department of Nuclear Medicine and Endocrinology, Charles University, 2nd Faculty of Medicine and Faculty Hospital Motol, Prague, Czech Republic Keywords: radiotherapy, radiation-induced thyroid cancer, childhood cancer The thyroid gland in children is among the most sensitive organs to the carcinogenic effects of ionizing radiation, and very young children are at especially high risk. Due to extreme sensitivity of the thyroid gland in children , there is a risk of radiation - induced thyroid cancer even the thyroid gland is outside of the irradiated field. Increased incidence of thyroid cancer has been noted following radiotherapy not only for childhood Hodgkin disease ( majority of observed patients ), but also for non-Hodgkin lymphoma, neuroblastoma, Wilms tumor, acute lymphocytic leukemia and tumors of the central nervous system also. Radiation-induced tumors begin to appear 5-10 years after irradiation and excess risk persists for decades, perhaps for the remainder of life. The incidence of thyroid cancer is two-to threefold higher among females than males. Most of the thyroid cancers that occur in association with irradiation are of the papillary type, for which the cure rate is high if tumors are detected early. Our Department in co-operation with Department of Children Hematology and Oncology Charles University 2nd Faculty of Medicine and Faculty Hospital Motol monitors patients after therapy for cancer in childhood for the long term period. The monitoring is focused on detection of thyroid disorders that occur as last consequences of oncology therapy, especially early detection of nodular changes in thyroid gland and thyroid carcinogenesis. The casuistry presents two patients observed in our department that were diagnosed the papillary thyroid carcinoma which occured 15 and more years after radiotherapy for childhood cancer. After total thyreoidectomy they underwent therapy with radioiodine . After radiotherapy it is necessary to pursue a long –term follow and assure interdisciplinary co-operation which enables early detection of last consequences of radiotherapy, especially the most serious ones as secondary carcinogenesis. Early substitution of hypotyreoidism is important for elimination of harmful effects of increased TSH level for thyroid gland. Disclosure of Interest: None Declared Keywords: radiotherapy, radiation-induced thyroid cancer , childhood cancer

Rearranged anaplastic lymphoma kinase (ALK) gene found for the first time in adult-onset papillary thyroid cancer cases among atomic bomb survivors

K. Hamatani 1,*, M. Mukai 1, Y. Hayashi 2, K. Takahashi 1, K. Nakachi 1, Y. Kusunoki 1

1Radibiology/Molecular Epidemiology, RADIATION EFFECTS RESEARCH FOUNDATION, 2

Geriatric Health Service Facility Hidamari, Hiroshima, Japan

Abstract: Thyroid cancer is one of the malignancies most strongly associated with ionizing radiation in humans. RERF epidemiology studies of atomic bomb (A-bomb) survivors have indicated that excess relative risk of papillary thyroid cancer per Gy was remarkably high in the survivors. We therefore aim to clarify mechanisms linking A-bomb radiation exposure and development of papillary thyroid cancer. Toward this end, we intend to clarify characteristics of gene alterations occurring in radiation-associated adult-onset papillary thyroid cancer from the Life Span Study cohort of A-bomb survivors.

We have thus far found that with increased radiation dose, papillary thyroid cancer cases with chromosomal rearrangements (mainly RET/PTC rearrangements) significantly increased and papillary thyroid cancer cases with point mutations (mainly BRAFV600E

) significantly decreased. Papillary thyroid cancer cases with non-detected gene alterations that carried no mutations in RET, NTRK1, BRAF or RAS genes tended to increase with increased radiation dose. In addition, we found that relative frequency of these papillary thyroid cancer cases significantly decreased with time elapsed since exposure. Through analysis of papillary thyroid cancer cases with non-detected gene alterations, we recently discovered a new type of rearrangement for the first time in papillary thyroid cancer, i.e., rearranged anaplastic lymphoma kinase (ALK) gene, although identification of any partner gene(s) is needed. Specifically, rearrangement of ALK was found in 10 of 19 exposed papillary thyroid cancer cases with non-detected gene alterations but not in any of the six non-exposed papillary thyroid cancer cases. Furthermore, papillary thyroid cancer with ALK rearrangement was frequently found in the cases with high radiation dose or with short time elapsed since A-bomb exposure. These results suggest that chromosomal rearrangement, typically of RET and ALK, may play an important role in the development of radiation-associated adult-onset papillary thyroid cancer.

Disclosure of Interest: None Declared

Keywords: ALK rearrangement, radiation-associated papillary thyroid cancer, RET/PTC rearrangements

Structure of the thyroid pathology in the radiation exposed areas of Leningrad region: late consequences of Chernobyl accident after 20 years A. Semenov 1,*, A. Uspenskaya 1, E. Bychenkova 1, I. Chinchuk 1, K. Novokshonov 1, R. Chernikov 1, I. Sleptsov 1, A. Bubnov 1, Y. Fedotov 1, V. Makarin 1, Y. Karelina 1 1

Endocrinology, NWRMC FHSDA, St-Petersburg, Russian Federation

Abstract: After the Chernobyl accident large areas of the USSR were contaminated with fallout, it has been proved that I131 caused higher incidence of papillary thyroid cancer in children and adolescents. Further observation for over 20 years showed retention of high annual prevalence of this pathology among the population. The settlements of Leningrad region with an established fact of contamination inhabit 9 thousand residents. The aim of this study is to evaluate the ultimate result of the influence of I131 on a thyroid gland. Materials and methods In 2007-2009 on the basis of the mobile diagnostic complex «Thyrobus» residents of the contaminated and control (noncontaminated) areas of Leningrad region had been surveyed. The study included 454 women living in localities affected by the Chernobyl accident in April-May 1986 (case) and 909 women living in fallout-free localities where similar median urinary iodine and the incidence of thyroid enlargement in their 7-8-year-old children (ICCIDD method). The average age in the case group was 50,5±13,3 y.o. (28,2±13,2 at the moment of the Accident) and 48,5±13,2 y.o. (26,9±12,9) in a group of control. Every patient had undergone thyroid ultrasound, thyroid hormones (fT3, fT4), TSH, antithyroid antibodies measurement. All patients with disclosed thyroid nodes ≥1 cm were suggested undergoing the FNAB under US. Dominant and every suspicious nodes had been punctured in each lobe. In the group of cases 96 patients had undergone the FNAB, 22 patients refused to be examined. In the control group 116 residents had undergone the FNAB and 64 residents had evaded the examination. Results In the case group the rate of overt hypothyroidism was higher (1,8%), than in the control group (1,3%), the rate of subclinical hypothyroidism was 2% (case) and 3,1% (control), euthyroid state patients receiving substitutive therapy were 3,1%, and 1,1%,correspondingly. A heterogeneous ultrasound structure had been found in the case group more often (54,4% ) than in the control one (42,6%). The rate of thyroiditis in the FNAB findings is 18,9% and 9,7% respectively. Antithyroid antibodies had been found in 30,6% (case) and in 21,7% (control). It should be noted that in persons younger than 32 years (not older than 10 y.o. at the time of Chernobyl accident) the rate of antithyroid antibodies was 19,1% in case and 13,9% in control groups, the rate of overt thyrotoxicosis in the case areas was 1,1% as compared to 0,1% in the control ones. Subclinical thyrotoxicosis 3,3% and 2,7%, respectively. Nodes had been found in 57,3% cases and in 42,4% controls. Papillary cancer rate in the FNAB findings was 4,2% and 2,7% correspondingly. Although the average age of the patients with malignant tumors differed from 53,8 ± 9,4 y.o. in the case group to 60,0 ± 6,0 y.o., in the control group. Conclusion The incidence of malignant thyroid tumors among of inhabitants of the contaminated territories is higher than in the control area. This phenomenon can not be unambiguously attributed to radiation induced cancers, but requires further investigation, perhaps by the method of carrying out continuous and all-round prophylactic medical examination. High incidence of autoimmune changes can be considered to have been caused by the action of I131 and prophylactic supplement with stable iodine. Disclosure of Interest: None Declared Keywords: autoimmune thyroid disease, Chernobyl, Papillary thyroid cancer

Thyroid adenomas and carcinomas following radiotherapy for a hemangioma during infancy

N. Haddy 1,*, T. Andriamboavonjy 1, C. Paoletti 1, M.-G. Dondon 2, A. Mousannif 1, A. Shamsaldin 1, F. Doyon 1, M. Labbé 1, C. Robert 3, M.-F. Avril 4, P. Fragu 5, F. Eschwege 6, J. CHAVAUDRA 6, C. Schvartz 7, D. Lefkopoulos 6, M. Schlumberger 5, I. DIALLO 1, F. De Vathaire 1

1Inserm, INSTITUT GUSTAVE ROUSSY, Villejuif Cedex, 2Inserm, Institut Curie, Paris, 3Dermatology, INSTITUT GUSTAVE ROUSSY, Villejuif Cedex, 4Dermatology, Hôpital Cochin, Paris, 5Nuclear Medicine, 6Radiotherapy, INSTITUT GUSTAVE ROUSSY, Villejuif Cedex, 7

Réseau des registres des cancers, Francim, Toulouse, France

Abstract: Background and purpose A cohort study was performed to investigate the carcinogenic effect of treating skin hemangioma with ionizing radiation during early childhood. This paper presents the incidence of differentiated thyroid adenomas and carcinomas after radiotherapy in this cohort.

Methods and Materials Of a total of 8307 patients treated for a skin hemangioma between 1940 and 1973 at the Institut Gustave-Roussy, 4767 were included in an incidence study, among whom 3795 had received radiotherapy. 73% were less than 1 year old at the time of treatment. External radiotherapy, Radium 226, Strontium 90, Yttrium 90, and Phosphorus 32 were used. The radiation dose received by the thyroid during radiotherapy, estimated in 3497 of the 3795 patients using specific software, was 41 mGy on average. Thyroid tumor cases were obtained by sending out a questionnaire, and verified in pathological reports. Estimates of thyroid cancer specific incidence rates in the French population were obtained from the French cancer registry network. External and internal analyses were performed.

Results During an average follow-up of 35 years, 11 patients developed a differentiated thyroid carcinoma and 44 a thyroid adenoma. The incidence of thyroid adenoma was found to be higher among taller and heavier individuals. The incidence of both thyroid carcinoma and adenoma was higher among non-smoker patients. A significant dose-response relationship was found between the radiation dose received by thyroid and the risk of thyroid cancer (Excess Relative Risk per GY, ERR/Gy: 14.7, 95%CI: 1.6 - 62.9) and of adenoma (ERR/Gy: 5.7, 95%CI:0.7 - 19.4).

Conclusion This study confirms that radiation treatment performed in the past for hemangioma during infancy increased the risk of thyroid carcinoma and adenoma. Patients treated with external radiotherapy or with Radium 226 applicators for hemangiomas have to be more specifically followed up because this is the subgroup in whom the highest doses were received by the thyroid gland (more than 90% of the radiation doses were higher than 100mGy). They are therefore more at risk of developing thyroid cancer.

Disclosure of Interest: None Declared

Keywords: hemangioma, childhood, radiation, thyroid tumor, cohort

131I-iodine ablation in outpatients with low-risk thyroid cancer using a repeated low activity (740 MBq x 2)

J. Clerc 1,*, M. Bienvenu-Perrard 1, E. Laroche 1, F. Dagousset 1, T. Delbot 1, M. Dreyfuss 1, C. Pichard de Malleray 1, F. Tenenbaum 1, F. A. Leger 1, B. Richard 1

1

Nuclear Medicine, ASSISTANCE PUBLIQUE COCHIN HOSPITAL, Paris, France

Abstract: Radioactive remnant ablation in low-risk thyroid cancer patients is widely used to facilitate follow-up and to provide a reliable staging. Attempts to give lower activities seemed encouraging but may negatively influence the ablation rates. We report the effectiveness of a repeated MINIDOSE 131I administration after preparation with thyroid hormone withdrawal (THW, n=36) or recombinant TSH (rhTSH, n=93). Methods: among 156 low-risk patients (pT1, N0/Nx) 129 had two 740 MBq administrations, at 6 – 12 mo interval, and a prolonged follow-up (mean 41.1 mo, range : 6.9 -362 mo). Two ablation criteria, ABLA 1 (ABLA 2) were respectively defined as follows: stimulated Tg < 1 ng/ml (< 2 ng/ml, resp.), cervical bed uptake < 0.1 % (< 0.2 %, resp.) and negative cervical Doppler-US. Results : at MINIDOSE 1, stimulated Tg [14.5 ± 31.5 ng/ml, mean± SD] was similarly elevated in both groups (p:0.95) but cervical uptake measurements (%) were higher in THW patients (1.58 ± 1.03) as compared to rhTSH (1.05 ± 1.06, p< 0.0012), in connection with a 2.2 higher creatinin normalized urinary iodine excretion (UIE/UC) in rhTSH patients (mean 96 vs 210 nM/mM, p<0.0001). In multivariate analysis, success of ablation mainly depends on 2 independent factors at baseline : a stimulated Tg < 10 ng/ml (OR : 10.2, p< 10-4) and a rhTSH driven ablation (OR : 4.7, p< 0.015), but neither on UIE/IC values (p:0.59) or on cervical bed uptake (p:0.96) nor on 131I scan grading (p:0.49). In rhTSH patients, overall success rate rose from 73.4% (88.3 % using ABLA 2) with MINIDOSE 1 to 77.7% (89.4 % using ABLA 2) at controls, with an even higher success rate of 97.2 % in patients with an initial stimulated Tg < 10 ng/ml. In these latter patients, the need for the second 131I administration is questionable. The protocol also allowed the identification of three patients with positive nodes and two with unsuspected metastatic disease. Conclusion : Two-step administration of 131

I (740 MBq x 2, at 6 – 12 months interval) is effective for thyroid ablation in low-risk patients, especially after preparation with rhTSH. It is cost-effective, well tolerated and may obviate the need for ablation-related hospitalisation in most countries.

Disclosure of Interest: None Declared