A mathematical model for radiation-induced life-shortening attributed to cancer.

PURPOSE: In this paper, we described our mathematical model for radiation-induced life shortening in detail and applied the model to the experimental data on mice to investigate the effect of radiation on cancer-related life-shortening. MATERIALS AND METHODS: Our mathematical model incorporates the following components: (i) occurrence of cancer, (ii) progression of cancer over time, and (iii) death from cancer. We evaluated the progression of cancer over time by analyzing the cancer incidence data and cumulative mortalities data obtained from mice experiments conducted at the Institute for Environmental Sciences (IES). RESULTS: We analyzed non-irradiated control and 20 mGy/day × 400 days irradiated groups. In the analysis, all malignant neoplasms were lumped together and referred to as 'cancer'. Our analysis showed that the reduction in lifespan (104 days in median) was the result of the early onset of cancer (68 days in median) and the shortening of the cancer progression period (48 days in median). CONCLUSIONS: We described in detail our mathematical model for radiation-induced life-shortening attributed to cancer. We analyzed the mice data obtained from the experiment conducted at the IES using our model. We decomposed radiation-induced life-shortening into the early onset of cancer and the shortening of the cancer progression period.

Risk of hematological malignancies from CT radiation exposure in children, adolescents and young adults.

Over one million European children undergo computed tomography (CT) scans annually. Although moderate- to high-dose ionizing radiation exposure is an established risk factor for hematological malignancies, risks at CT examination dose levels remain uncertain. Here we followed up a multinational cohort (EPI-CT) of 948,174 individuals who underwent CT examinations before age 22 years in nine European countries. Radiation doses to the active bone marrow were estimated on the basis of body part scanned, patient characteristics, time period and inferred CT technical parameters. We found an association between cumulative dose and risk of all hematological malignancies, with an excess relative risk of 1.96 (95% confidence interval 1.10 to 3.12) per 100 mGy (790 cases). Similar estimates were obtained for lymphoid and myeloid malignancies. Results suggest that for every 10,000 children examined today (mean dose 8 mGy), 1-2 persons are expected to develop a hematological malignancy attributable to radiation exposure in the subsequent 12 years. Our results strengthen the body of evidence of increased cancer risk at low radiation doses and highlight the need for continued justification of pediatric CT examinations and optimization of doses.

Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo.

The CGL1 human hybrid cell system has been utilized for many decades as an excellent cellular tool for investigating neoplastic transformation. Substantial work has been done previously implicating genetic factors related to chromosome 11 to the alteration of tumorigenic phenotype in CGL1 cells. This includes candidate tumor suppressor gene FOSL1, a member of the AP-1 transcription factor complex which encodes for protein FRA1. Here we present novel evidence supporting the role of FOSL1 in the suppression of tumorigenicity in segregants of the CGL1 system. Gamma-induced mutant (GIM) and control (CON) cells were isolated from 7 Gy gamma-irradiated CGL1s. Western, Southern and Northern blot analysis were utilized to assess FOSL1/FRA1 expression as well as methylation studies. GIMs were transfected to re-express FRA1 and in vivo tumorigenicity studies were conducted. Global transcriptomic microarray and RT-qPCR analysis were used to further characterize these unique cell segregants. GIMs were found to be tumorigenic in vivo when injected into nude mice whereas CON cells were not. GIMs show loss of Fosl/FRA1 expression as confirmed by Western blot. Southern and Northern blot analysis further reveals that FRA1 reduction in tumorigenic CGL1 segregants is likely due to transcriptional suppression. Results suggest that radiation-induced neoplastic transformation of CGL1 is in part due to silencing of the FOSL1 tumor suppressor gene promoter by methylation. The radiation-induced tumorigenic GIMs transfected to re-express FRA1 resulted in suppression of subcutaneous tumor growth in nude mice in vivo. Global microarray analysis and RT-qPCR validation elucidated several hundred differentially expressed genes. Downstream analysis reveals a significant number of altered pathways and enriched Gene Ontology terms genes related to cellular adhesion, proliferation, and migration. Together these findings provide strong evidence that FRA1 is a tumor suppressor gene deleted and epigenetically silenced after ionizing radiation-induced neoplastic transformation in the CGL1 human hybrid cell system.

Risks of leukemia, intracranial tumours and lymphomas in childhood and early adulthood after pediatric radiation exposure from computed tomography.

BACKGROUND: Children are more susceptible to radiation-induced damage than adults, but little research has compared the risk of cancer after exposure to radiation during computed tomography (CT) among children at different ages. We aimed to explore the risk of intracranial tumours, leukemia or lymphoma among children, adolescents and young adults (aged < 25 yr) after radiation exposure from CT at or before the age of 18 years. METHODS: We conducted a nested, population-based case-control study using data from Taiwan's publicly funded health care system. We identified participants younger than 25 years with newly diagnosed intracranial tumours, leukemia or lymphoma, from Jan. 1, 2000, to Dec. 31, 2013. We assigned 10 non-cancer controls for each case, matching by sex, date of birth and day of entry to the cohort. We considered CT scans received at or before the age of 18 years and 3 or more years before the index date (the date of cancer diagnosis for cases) as exposure. We used conditional logistic regression models and incidence rate ratios (IRRs) to estimate the relationship between risk of these cancers and CT radiation exposure. RESULTS: We identified 7807 cases and matched to 78 057 controls. Compared with no exposure, exposure to a single pediatric CT scan did not increase risk of intracranial tumours, leukemia or lymphoma. However, participants exposed to 4 or more CT scans had an elevated incidence (IRR 2.30, 95% confidence interval 1.43-3.71) of one of the cancer outcomes of interest. Receiving 4 or more CT scans at or before 6 years of age was associated with the highest risks of cancer, followed by ages 7-12 years and 13-18 years (p for trend < 0.001). INTERPRETATION: Exposure to a single CT scan was not associated with increased risks of subsequent intracranial tumours, leukemia or lymphoma among children; however, we observed increased cancer risks among those with 4 or more CT scans, especially among younger children. Although these cancers are uncommon, the findings of this study underscore the importance of prudent use of CT in the pediatric population.

Basal cell carcinomas of the scalp after radiotherapy for tinea capitis: Clinicopathological study in a case series of 96 patients with analysis of 427 tumours.

BACKGROUND/OBJECTIVES: Low-dose X-ray radiotherapy to treat tinea capitis during childhood is a well-known risk factor for scalp basal cell carcinomas (BCCs). Post-radiotherapy BCCs are often multiple, and it has been suggested that they display more aggressive features. Our main objective was to study the clinicopathological aspects of post-radiotherapy BCCs to evaluate their biological behaviour and identify features that may differ from other BCCs. METHODS: We performed an observational, retrospective study assessing multiple clinical and pathological characteristics of patients with post-radiotherapy BCCs. RESULTS: We studied 96 patients with 427 post-radiotherapy scalp BCCs. Post-radiotherapy BCCs were often multiple (median of 4 lesions/patient, ranging from 1 to 54). Significant comorbidities included a high incidence of thyroid disease and meningiomas. Recurrences were observed in 23% of patients, but there may be confounding factors, such as referral bias, heterogenous treatment modalities and occurrence of new tumours due to field effect. We found a high incidence of infundibulocystic BCCs (in 14.6% of patients and corresponding to 5.4% of the total number of tumours), trichoblastomas (5.2%) and neurofibromas of the scalp (10%). CONCLUSIONS: This study is consistent with the occurrence of multiple lesions (sometimes numerous) and a relatively high tendency for recurrence in post-radiotherapy BCCs, as suggested by previous studies. We also found a high incidence of the infundibulocystic variant and a higher risk of follicular tumours and neurofibromas, which suggests that radiotherapy may influence the type of differentiation of BCCs and contribute to induce neoplasms of different cell lines.

Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study.

BACKGROUND: The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. METHODS: We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. FINDINGS: We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. INTERPRETATION: The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. FUNDING: EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

Does systemic hydrochlorothiazide increase the risk of developing ultraviolet radiation-induced skin tumours in hairless mice?

Hydrochlorothiazide (HCTZ) is a frequently prescribed diuretic that exhibits photosensitizing properties. It is used to treat hypertension and edema. Dermato-epidemiological studies in various populations have linked HCTZ treatment with increased risk of particular types of skin cancer, including malignant melanoma (lentigo subtype), and both basal cell carcinoma and squamous cell carcinoma (SCC). This study investigated whether either of two different doses of HCTZ increased the risk of SCC development in mice exposed to ultraviolet radiation (UVR). A total of three groups of hairless mice were used in this study (total, N = 71). One group received a low dose (0.26 mg/mouse/day) and another group received a high dose (0.52 mg/mouse/day) of HCTZ in their drinking water; a third UVR control group received only tap water. All three groups were irradiated with UVR until the mice developed three tumours that were 4 mm in size. The times to SCC tumour development were recorded. In the low-dose group, the median time to develop an SCC tumour was 170 days; in both the high-dose group and the control group, the median time to develop anexd SCC tumour was 163 days (p ≥ 0.331). In our hairless mouse model, we found that mice treated with UVR plus HCTZ did not develop SCCs more rapidly than mice treated with UVR but not HCTZ.

Predominant contribution of the dose received from constituent heavy-ions in the induction of gastrointestinal tumorigenesis after simulated space radiation exposure.

Gastrointestinal (GI) cancer risk among astronauts after encountering galactic cosmic radiation (GCR) is predicted to exceed safe permissible limits in long duration deep-space missions. Current predictions are based on relative biological effectiveness (RBE) values derived from in-vivo studies using single-ion beams, while GCR is essentially a mixed radiation field composed of protons (H), helium (He), and heavy ions. Therefore, a sequentially delivered proton (H) → Helium (He) → Oxygen (O) → Silicon (Si) beam was designed to simulate simplified-mixed-field GCR (Smf-GCR), and Apc1638N/+ mice were total-body irradiated to sham or γ (157Cs) or Smf-GCR followed by assessment of GI-tumorigenesis at 150 days post-exposure. Further, GI-tumor data from equivalent doses of heavy-ions (i.e., 0.05 Gy of O and Si) in 0.5 Gy of Smf-GCR were compared to understand the contributions of heavy-ions in GI-tumorigenesis. The Smf-GCR-induced tumor and carcinoma count were significantly greater than γ-rays, and male preponderance for GI-tumorigenesis was consistent with our earlier findings. Comparison of tumor data from Smf-GCR and equivalent doses of heavy ions revealed an association between higher GI-tumorigenesis where dose received from heavy-ions contributed to > 95% of the total GI-tumorigenic effect observed after Smf-GCR. This study provides the first experimental evidence that cancer risk after GCR exposure could largely depend on doses received from constituent heavy-ions.

Lung-Cancer Risk in Mice after Exposure to Gamma Rays, Carbon Ions or Neutrons: Egfr Pathway Activation and Frequent Nuclear Abnormality.

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2-4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05-1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development.

Ionizing Radiation-Induced Tumor Cell-Derived Microparticles Prevent Lung Metastasis by Remodeling the Pulmonary Immune Microenvironment.

PURPOSE: The majority of cancer-related deaths are attributed to metastasis rather than localized primary tumor progression. However, the factors that regulate the premetastatic niche (PMN) and metastasis have not yet been clearly elucidated. We investigated the antimetastatic effects of irradiated tumor cell-derived microparticles (RT-MPs) and highlighted the role of innate immune cells in PMN formation. METHODS AND MATERIALS: Mice were treated 3 times with isolated RT-MPs, followed by tumor cell injection via the tail vein. The hematoxylin and eosin staining was performed to assess the number of tumor nodules in the lungs, and in vivo luciferase-based noninvasive bioluminescence imaging was conducted to detected tumor burden. The mechanisms of RT-MPs mediated PMN formation was evaluated using flow cytometry, transwell assay, and reverse transcription-polymerase chain reaction. RESULTS: RT-MPs inhibited tumor cell colonization in the lungs. Neutrophils phagocytosed RT-MPs and secreted CCL3 and CCL4, which induced monocytes chemotaxis and maturation into macrophages. RT-MPs promoted the transition of neutrophils and macrophages into antitumor phenotypes, hence inhibiting cancer cell colonization and proliferation. CONCLUSIONS: RT-MPs inhibited PMN formation and lung metastasis in a neutrophil- and macrophage-dependent but T cell-independent manner.

Risk of second primary malignancies associated with radiotherapy in prostate cancer patients: competing risk analysis.

Background: The effect of radiotherapy (RT) for second primary malignancies (SPMs) among prostate cancer survivors is controversial. Methods: Applying logistic regression, competing risk analysis and propensity score matching method, this study analyzed clinical data from the Surveillance, Epidemiology, and End Results program to compare the risk for SPMs between patients receiving RT and non-RT. Results: In this study, prostate cancer patients treated with RT developed more SPMs in the anus, bladder, rectum, liver, lung and bronchus and lymphoma than non-RT groups. Conclusion: More intensive surveillance should be adopted for these cancers among prostate cancer survivors.

Plain language summary Patients with prostate cancer have the highest 5-year survival rate, which increases the risk for developing second primary malignancies (SPMs). The effect of radiotherapy (RT) for SPMs is controversial among prostate cancer survivors. This study analyzed a mass of prostate cancer patients from a public database to compare risk for SPMs between RT and non-RT groups. RT indeed increased certain categories of SPM and intensive surveillance should be considered.

Non-Hodgkin lymphomas and ionizing radiation: case report and review of the literature.

Non-Hodgkin lymphoma (NHL) increased continuously since the last century in developed countries. While they are considered as disease in elder ages, a remarkable increasing incidence is also observed in German children and juveniles. The higher rates are interpreted by the changes in classification because diseases such as chronic lymphocytic leukaemia were also identified as NHL. Considerable rates of NHL were found in nuclear workers and liquidators of Chernobyl, i.e. in cases of low-dose chronical exposures. In Germany, we noticed three workers who developed NHL after decontamination of nuclear facilities. The bone marrow is generally considered as target organ for ionizing radiation, but NHL is obviously induced in the whole pool of lymphocytes. Therefore, the dosimetry in cases of typical occupational external and internal exposure must be revised. A high radiation sensitivity for NHL is a possible suspect and likely reason which may partly explain the continuous rise of the diseases in populations underlying the current increases of medical diagnostic exposure. NHL is also induced in children and juveniles with a history of diagnostic X-rays.

Mutant p53 reactivator SLMP53-2 hinders ultraviolet B radiation-induced skin carcinogenesis.

The growing incidence of skin cancer (SC) has prompted the search for additional preventive strategies to counteract this global health concern. Mutant p53 (mutp53), particularly with ultraviolet radiation (UVR) signature, has emerged as a promising target for SC prevention based on its key role in skin carcinogenesis. Herein, the preventive activity of our previously disclosed mutp53 reactivator SLMP53-2 against UVR-induced SC was investigated. The pre-treatment of keratinocyte HaCaT cells with SLMP53-2, before UVB exposure, depleted mutp53 protein levels with restoration of wild-type-like p53 DNA-binding ability and subsequent transcriptional activity. SLMP53-2 increased cell survival by promoting G1-phase cell cycle arrest, while reducing UVB-induced apoptosis through inhibition of c-Jun N-terminal kinase (JNK) activity. SLMP53-2 also protected cells from reactive oxygen species and oxidative damage induced by UVB. Moreover, it enhanced DNA repair through upregulation of nucleotide excision repair pathway and depletion of UVB-induced DNA damage, as evidenced by a reduction of DNA in comet tails, γH2AX staining and cyclobutane pyrimidine dimers (CPD) levels. SLMP53-2 further suppressed UVB-induced inflammation by inhibiting the nuclear translocation and DNA-binding ability of NF-κB, and promoted the expression of key players involved in keratinocytes differentiation. Consistently, the topical application of SLMP53-2 in mice skin, prior to UVB irradiation, reduced cell death and DNA damage. It also decreased the expression of inflammatory-related proteins and promoted cell differentiation, in UVB-exposed mice skin. Notably, SLMP53-2 did not show signs of skin toxicity for cumulative topical use. Overall, these results support a promising protective activity of SLMP53-2 against UVB-induced SC.

Incidence of lymphoid neoplasms among atomic bomb survivors by histological subtype, 1950 to 1994.

Epidemiological data have provided limited and inconsistent evidence on the relationship between radiation exposure and lymphoid neoplasms. We classified 553 lymphoid neoplasm cases diagnosed between 1950 and 1994 in the Life Span Study cohort of atomic bomb survivors into World Health Organization subtypes. Mature B-cell neoplasms represented 58%, mature T-cell and natural killer (NK)-cell neoplasms 20%, precursor cell neoplasms 5%, and Hodgkin lymphoma (HL) 3%, with the remaining 15% classified as non-Hodgkin lymphoid (NHL) neoplasms or lymphoid neoplasms not otherwise specified. We used Poisson regression methods to assess the relationship between radiation exposure and the more common subtypes. As in earlier reports, a significant dose response for NHL neoplasms as a group was seen for males but not females. However, subtype analyses showed that radiation dose was strongly associated with increased precursor cell neoplasms rates, with an estimated excess relative risk per Gy of 16 (95% Confidence interval: 7.0, >533) at age 50. The current data based primarily of tissue-based diagnoses suggest that the association between radiation dose and lymphoid neoplasms as a group is largely driven by the radiation effect on precursor cell neoplasms while presenting no evidence of a radiation dose response for major categories of mature cell neoplasms, either B- or T-/NK-cell, or more specific disease entities (diffuse large B-cell lymphoma, plasma cell myeloma, adult T-cell leukemia/lymphoma) or HL.

Does Radioactive Iodine Therapy for Hyperthyroidism Cause Cancer?

Radioactive iodine has been considered a safe and effective therapeutic option for hyperthyroidism secondary to Graves disease and autonomously functioning thyroid nodules since the mid-20th century. The question of whether I-131 at the doses used for hyperthyroidism might increase the risk of cancer has been investigated in a number of observational cohort studies over the years, with the preponderance of evidence being reassuring as to its safety. In particular, the 1998 Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFUS) has been widely cited as compelling evidence that I-131 is safe in hyperthyroidism therapy with respect to carcinogenesis. However, in 2019, a study by Kitahara and colleagues re-analyzed the CTTFUS cohort, extending the follow-up time and applying a novel dosimetric model for estimating tissue absorbed doses of radiation. This new analysis concluded that radioactive iodine was associated with an increased risk for mortality from overall cancer, breast cancer, and non-breast solid cancers. Reaction to this study was vociferous and particularly negative in the nuclear medicine literature. This mini-review was inspired by the 2019 CTTFUS controversy, and it is intended to provide the necessary context for clinicians to provide nuanced advice to their patients on the subject. To that end, the pre-2019 literature is surveyed, the 2019 CTTFUS study and a 2020 follow-up are discussed, and lessons from the literature and critical commentaries are considered.

Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes.

The management of patients with cancer and Li-Fraumeni or heritable TP53-related cancer syndromes is complex because of their increased risk of developing second malignant neoplasms after genotoxic stresses such as systemic treatments or radiotherapy (radiosusceptibility). Clinical decision making also integrates the risks of normal tissue toxicity and sequelae (radiosensitivity) and tumour response to radiotherapy (radioresistance and radiocurability). Radiotherapy should be avoided in patients with cancer and Li-Fraumeni or heritable TP53 cancer-related syndromes, but overall prognosis might be poor without radiotherapy: radioresistance in these patients seems similar to or worse than that of the general population. Radiosensitivity in germline TP53 variant carriers seems similar to that in the general population. The risk of second malignant neoplasms according to germline TP53 variant and the patient's overall oncological prognosis should be assessed during specialised multidisciplinary staff meetings. Radiotherapy should be avoided whenever other similarly curative treatment options are available. In other cases, it should be adapted to minimise the risk of second malignant neoplasms in patients who still require radiotherapy despite its genotoxicity, in view of its potential benefit. Adaptations might be achieved through the reduction of irradiated volumes using proton therapy, non-ionising diagnostic procedures, image guidance, and minimal stray radiation. Non-ionising imaging should become more systematic. Radiotherapy approaches that might result in a lower probability of misrepaired DNA damage (eg, particle therapy biology and tumour targeting) are an area of investigation.

Comparative pathological characteristics of papillary thyroid carcinoma with second primary non-thyroid malignancies in the region affected by the Chernobyl accident.

The aim was to study the pathological features of papillary thyroid carcinoma diagnosed with or before second primary malignancy in patients exposed to post-Chernobyl exposure. The patients selected (n = 6559) were those exposed to radiation at the age of ≤ 18 years old and developed papillary thyroid carcinoma during the years 1990-2020. Of these, 2.1% (n = 140) had second primary malignancies. To compare the histopathological characteristics of papillary thyroid carcinoma in the group under analysis, 91% (n = 128) with sufficient data were included in further analysis. The control group was formed by matching patients with age at exposure to radiation, age at surgery, gender, and place of residence. Median age at exposure was 14 years old for both groups. Besides, no difference in tumour extension and histological features of papillary thyroid carcinoma was noted between patients with synchronous or metachronous primary malignant tumours. Nevertheless, the time lag to the diagnosis of papillary thyroid carcinoma was shortened in the group with metachronous when compared to patients with synchronous second primaries (p < 0.001). Independent differences between patients with second primaries and their matched peers included tumour size {OR (95%CI) = 0.89 (0.45; 1.04)}, multiple tumours {OR (95% CI) = 1.46 (0.86; 2.42)}, lymphatic vessel invasion (OR (95%CI) 0.92 (0.61; 1.53)), blood vessel invasion (OR (95%CI) 0.41 (0.10; 1.23) and presence of numerous psammomas (OR (95%CI) 0.73 (0.39; 1.31)). The possible influence of radiative iodine treatment for development of second primaries was analysed for the group of patients with metachronous malignancies using the same approach (84 patients were compared to 252 matched patients). Independent differences also included tumour size {OR (95% CI) 0.77 (0.45; 1.30)}, lymphatic vessel invasion {OR (95%CI) 0.75(0.43; 1.28)}, blood vessel invasion {OR (95%CI) 0.17 (0.01; 0.87)}. Besides, multiple tumours were revealed more frequently in patients with metachronous primaries (OR (95%CI) 1.92 (1.0; 3.62)). To conclude, patients exposed to Chernobyl irradiation with the development of papillary thyroid carcinoma and second primary malignancy have less biological aggressive pathological characteristics of their thyroid cancers. Accordingly, these patients were less frequently treated with post-surgical radioactive iodine. Thus, 131I-irradiation may have negligible impact on the development of second primaries.

Age-dependent effects on radiation-induced carcinogenesis in the rat thyroid.

Childhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis.

The impact of MYC gene amplification on the clinicopathological features and prognosis of radiation-associated angiosarcomas of the breast.

AIMS: Radiation-associated angiosarcomas (RT-ASs) of the breast are rare tumours with a poor prognosis. MYC gene amplification is considered to be the hallmark of RT-AS, and is sometimes used as a diagnostic tool to distinguish it from other radiation-associated vascular lesions. However, a small subset of RT-ASs lacks MYC amplification, and this may be associated with better outcome. Loss of trimethylation at lysine 27 of histone 3 (H3K27me3) expression by immunohistochemistry (IHC) has been recently postulated as an additional diagnostic marker for RT-AS. The aims of this study were to evaluate the impact of MYC amplification as detected by fluorescence in-situ hybridisation and/or next-generation sequencing on clinicopathological features and outcome in a large cohort of RT-ASs, compare outcome with those of radiation-associated sarcomas (RT-Ss) of the breast other than angiosarcoma, and evaluate expression of H3K27me3 IHC in these groups. METHODS AND RESULTS: Eighty-one RT-ASs were identified, including 73 that were MYC-amplified and 8 (10%) that were MYC-non-amplified. MYC-amplified RT-ASs were diagnosed in older patients (median age, 69 years versus 61 years). The 5-year disease-specific survival and 5-year overall survival rates were 56% and 47%, respectively. Older age, larger tumour size, positive margin and MYC amplification were associated with worse prognosis. None of the RT-ASs showed complete loss of H3K27me3 IHC expression. All 18 RT-Ss were MYC-non-amplified, and complete loss of H3K27me3 expression was seen in 2 cases. We found no difference in prognosis between RT-AS and RT-S. CONCLUSIONS: RT-AS of the breast is associated with a poor prognosis. Older age at diagnosis, larger tumour size, positive margin at excision and MYC amplification are associated with worse prognosis.