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Institute of Endocrinology and Metabolism,

Kyiv, Ukraine

Tronko M.D.

FUNDAMENTAL AND APPLIED ASPECTS OF THE STUDY OF THYROID CANCER IN CHILDREN AND ADOLESCENTS IN UKRAINE

(30 years of surveillance)

18 April 2016, Kyiv, Ukraine

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Comparison of radioactive iodine I131 fallout from nuclear reactors

Episode

I131 fallout (Curie)

Accident at Three Mile Island Nuclear Power Station, U.S.A (1979)

Accident at the reactor “Windscale”, UK (1957)

20 000

Technological fallout from a reactor in the process of plutonium production at the enterprise in Hanford, Washington, U.S.A.

690 000

Accident at Chernobyl Nuclear Power Station, Ukraine (1986)*

Accident at Fukushima Nuclear Power Station, Japan (2011)**

* In addition, fallouts of short-lived iodine and tellurium isotopes are estimated to be equal to 100,000,000 Curie (UNSCEAR 2008).

** Report of Japanese Government to IAEA Ministerial Conference on Nuclear Safety - Accident at TEPCO's Fukushima Nuclear Power Stations, 7 June 2011

15-20

40 000 000 – 50 000 000

4 000 000 – 5 000 000

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Cumulative fallout of I131 in the territory of Ukraine as a result of the Chernobyl accident (April 26th – May 7th, 1986)

Likhtarev et al., “Radiation and risk", 2005

Cumulative I-131 fallout on the soil (MBq/m2)

0.16 mean regional values

of I131 fallout (kBq/m2)

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Rayon average thyroid dose for children aged 0-18 at the time of the Chernobyl accident

UNSCEAR, 2008, Annex D.

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Main components of Clinical-Morphological Registry (CMR)

Personal

records

Clinical data

Demography

Pathology

Dosimetry

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Cooperation between CMR and other Registries

Clinical-Morphological Register,

IEM, Kiev

National Cancer Registry of Ukraine,

National Cancer Institute, Ukraine, Kiev

TherDep,

IEM, Kiev

Chernobyl Tissue Bank

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Current number of thyroid cancer cases in CMR (1986 – 2014)

Population groups

Thyroid cancer cases

Male

Female

Both

0-14 years old at the time of the accident

1510

6496

8006

15-18 years old at the time of the accident

399

2002

2401

Exposed in utero

52

150

202

Born in 1987 and later

270

1016

1286

Total

2231

9664

11895

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Ukrainian-American Thyroid Project

UkrAm cohort thyroid study – a classical prospective cohort study of radiation risk of thyroid cancer and other thyroid pathology in Ukrainian exposed as children and adolescent due to Chernobyl accident and having direct thyroid activity measurements in May-June 1986.

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Distribution of selected and examined cohort by dose group

Dose group A

7542 (57.0%)

Dose group B

3457 (26.1%)

Dose group C

2244 (16.9%)

Number of cohort members examined

13243

Total number of records selected from dose file

34092

Dose group A D<0,3Gy

Low dose

15541(45.6%)

Dose group B 0,3<D<1,0Gy

Middle dose 8476(24.9%)

Dose group C

D>1,0Gy

High dose

10075 (29.6%)

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Residence of cohort members in 1986

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Number of cohort members

that underwent different screening rounds

1998-2000 2001-2003 2003-2005 2005-2007 2012-2015

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Number of thyroid cancer cases according a place of residence in 1986

48

103

28

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Histological types of thyroid carcinomas (179 cases)

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Cumulative incidence of thyroid cancer cases

detected during 1st - 4th screening cycles

Cumulative incidence per 1000 subjects

Number of cases

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Cumulative incidence of thyroid cancer cases

detected during nodular project (2009-2011)

and 5th screening cycle (2012-2015)

Cumulative incidence per 1000 subjects

Number of cases

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UkrAm: estimates of thyroid cancer risk

  • In the cohort 13127 screened subjects during 1998-2000 45 thyroid cancer cases were detected.
  • The excess relative risk per gray (Gy) was estimated using individual doses and a linear excess relative risk model.
  • Thyroid cancer showed a strong, monotonic, and approximately linear relationship with individual thyroid dose estimate ( P <.001), yielding an estimated excess relative risk of 5.25 per Gy (95%CI = 1.70 to 27.5). In the absence of Chernobyl radiation, 11.2 thyroid cancer cases would have been expected compared with the 45 observed.

Prevalence: cases diagnosed in 1998-2000

Tronko M.D., Howe G.R., Bogdanova T.I. et al. JNCI, Vol. 98, 2006

Dose-response prevalence of thyroid cancers detected during first screening cycle (1998-2000)

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UkrAm: estimates of thyroid cancer risk

Brenner A.V., Tronko M.D., Hatch М., Bogdanova T.I. et al. EHP, March 2011, doi: 10.1289/ehp.1002674

I-131 Dose-Response for Incident Thyroid Cancers in Ukraine Related to the Chernobyl Accident

Incidence: cases diagnosed in 2001-2008

  • There were 65 incident thyroid cancers diagnosed during the 2nd-4th screenings in 2001-2008 (N=12514 ) and about 73,000 person-years of observation.

  • The ERR per Gy was estimated 1.91 (95% CI: 0.43-6.34) and EAR per 104 PY per Gy was 2.21 (95% CI: 0.04 - 5.78).

The ERR per Gy varied significantly by oblast of residence, but not by time since exposure. I-131-related thyroid cancer risks persisted for two decades following exposure.

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Ukrainian-American in Utero Study:

  • Objectives: Evaluate risk of screening-detected thyroid cancer using individual estimates of fetal thyroid dose (2003-2006)
  • Study area: most affected northern oblasts, (Zhitomir, Chernigov, Kiev)
  • 2,587 mother-child pairs: Women pregnant on April 26,1986 or the two months following when fallout still present

- 1,498 from contaminated areas (individual thyroid dose ranged from 0-3,23 Gy)

- 1,089 from no/low-contaminated areas (individual thyroid dose ranged from 0-0,37 Gy)

(Hatch et al., JCEM, 2009; Likhtarev et al., Health Phys, 2011)

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Summary of UkrAm in utero study

Based on 7 cases detected Risk of thyroid cancer from in utero exposure to I-131: (EOR/Gy=11.7 (95%CI: NE-1,982), P=0.12).

No clear evidence that the fetal thyroid is more sensitive to the carcinogenic effects of I-131 than that of the young child.

(Hatch et al., JCEM, 2008)

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THE JOINT UKRAM THYROID COHORT

IN UTERO THYROID COHORT,

2600 subjects

prenatally exposure,

1st screening cycle 2003-2006

MAIN THYROID COHORT,

13200 subjects

aged < 18 at exposure,

1st-4th screening cycles 1998-2008

JOINT UKRAM THYROID COHORT,

15800 subjects

since 2009

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Strengths of UkrAm Thyroid Study

Uniform screening using standardized procedures

Five cycles of clinical examinations with high retention rate in period 1998-2015

Good compliance with FNA and thyroid surgery

Individual questionnaire- and measurement- based thyroid doses

Wide range of individual doses (0.00035 - 42.0 Gy )

Advanced statistical models for accounting dose uncertainties

Detailed pathological analysis of the cases revealed.

Additional confirmation of diagnoses of International Pathology Panel (CTB)

Evaluation of iodine status

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Evaluation of the scientific results and the research potential of the UkrAm by international experts

NCRP Report No. 159, Risk to the Thyroid from Ionizing Radiation, Bethesda (MD), 2008

UNSCEAR 2008 Report: "Sources and effects of ionizing radiation".

Volume II. Annex D - Health effects due to radiation from the Chernobyl accident

The Expert Group recommends to include

Children at exposure cohort ( UkrAm cohort, about 15,800)

into ‘Chernobyl Life Span Cohorts’

EC Project ARCH (Agenda for Research on Chernobyl Health (http://arch.iarc.fr/)) Williams et al., J Radiol Prot, 2011

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Evolution of views and modern concepts

MOLECULAR BIOLOGY OF RADIATION-INDUCED THYROID CANCER

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Involvement of mutations in three sites of gene RET, which activate Ras-Raf-MAP signal pathway [by Fagin J.A., 2004].

Grb7, 10

1062

РІ3-K

RET/PTC

905

1015

PLC

RAS

PKC

B-RAF

Proliferation

MEK

ERK

SOS

Grb2

Shc

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Santoro M, Thomas GA, Vecchio G, Williams GH, Fusco A, Chiapetta G, Pozcharskaya V, Bogdanova TI, Demitchik EP, Cherstvoy ED, Voscoboinik L, Tronko ND, Carss A, Bunnell H., Tonnachera M, Parma J, Dumont JE, Keller G, Hofler H, Williams ED. Gene rearrangement and Chernobyl related thyroid cancer. British J Cancer. 2000; 82(2): 315-322.

Radiation-induced

PTC (n=45)

RET/PTC1

7 (16%)

RET/PTC3

12 (27%)

RET/PTC1&3

1 (2%)

Total:

20 (44%)

SF – solid-follicular structure

Pap – papillary structure

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Expression of oncogenes RET/РТС

in papillary thyroid cancer in patients

from different age’s groups

1 group: 13 ± 1�2 group : 25 ± 1�3 group : 38 ± 1�

%

%

%

%

%

R2=0,16

R2=0,98

R2=0,99

*

**

*

*

Age

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Mutation BRAFV600E

Romei C, Voskoboynyk L, Ciampi R, Bogdanova T, Elisei R, Tronko M, Pinchera A.

Gene alterations in post-Chernobyl benign and malignant thyroid tumors from Ukraine. 5th ETA CRN Meeting, Naples, Italy, September 1st. – 2006.

PTC

6/25*(24.0%)

FA

0/24(0%)

Mutation

BRAF V600Е

BRAF

wild type

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Genomic characterization of Chernobyl thyroid cancers �(NCI, IEM, CTB: in process)

500 PTC cases:

All UkrAm cohort PTC cases;

PTC cases from Chernigov, Kiev, Zhitomir regions, and Kiev-city (born before and after Chernobyl)

Paraffin embedded blocks

Frozen tissue samples

EDTA blood samples

Tumor – 1 block per case

Normal – 1 block per case

Mts - 1 block per case

Tumor – 1 sample per case

Normal – 1 sample per case

Mts - 1 sample per case

EDTA samples - 5 ml per case

Aims of Project: Comprehensive genomic characterization of

radiation-related thyroid cancer in the Ukraine

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The key trends of further studies

Study of the time pattern of risk and effect of modifying factors in the period 13-29 years after exposure

New models of taking into account individual dose estimate uncertainties in the dose-response analysis

Molecular-biological and genetic studies based on Project materials

The pooled analysis of Belarus-American and Ukrainian-American data

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Cooperation of Institute of Endocrinology

with international organizations and leading research institutions

Institute of Endocrinology

UNICEF

WHO

USA:

National Cancer Institute, Columbia and California Universities, CDC, Atlanta

Great Britain :

Imperial College (London),

Wales University,

Cambridge University

Belgium:

Free University of Brussels

Japan:

Nagasaki Medical University, Sasakawa Foundation

Italy:

Napoli University, Milano University, Pisa University

France:

University of Reims

Canada:

Toronto University

Germany:

Helmholtz Zentrum München, Neuherberg;

University of Wuerzburg; Marburg University;

Berlin Humboldt University

European Union

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THANK YOU FOR YOUR ATTENTION!