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This paper reports four cases of osteosarcoma of the jaw, a rare malignant bone tumor in the oral and maxillofacial region. Two patients were males and two were females. The age at the first visit ranged 55–69 years (average age, 63.8 years). Three and one patients had a tumor in the mandible and the maxilla, respectively. One mandibular patient had a history of radiotherapy for laryngeal cancer. Radiologically, two cases were of the osteolytic type, and two were of the osteosclerotic type. Two cases of the osteolytic type were diagnosed as malignant tumors, while the other two cases of the osteosclerotic type were as benign lesions (e.g., epulis osteoplastica and osteomyelitis). Pathologically, three and one cases were classified as conventional (osteoblastic type) and secondary (radiation-induced) osteosarcomas, respectively. All patients underwent surgical tumor resection without any adjunctive treatments. Consequently, one patient had no recurrence for 14 years after surgical treatment and the other three had local recurrence and/or distant metastasis, resulting in unfavorable outcomes despite further treatments. Osteosarcoma should be included as a differential diagnosis for bone-forming lesions of the jaw. Furthermore, complete surgical resection combined with adjuvant therapies would be necessary to improve the treatment outcome of jaw osteosarcomas.

Ionizing radiations encountered by astronauts on deep space missions produce biological damage by two main mechanisms: (1) Targeted effects (TE) due to direct traversals of cells by ionizing tracks. (2) Non-targeted effects (NTE) caused by release of signals from directly hit cells. The combination of these mechanisms generates non-linear dose response shapes, which need to be modeled quantitatively to predict health risks from space exploration. Here we used a TE+NTE model to analyze data on APC(1638N/+) mouse tumorigenesis induced by space-relevant doses of protons, 4He, 12C, 16O, 28Si or 56Fe ions, or γ rays. A customized weighted Negative Binomial distribution was used to describe the radiation type- and dose-dependent data variability. This approach allowed detailed quantification of dose-response shapes, NTE- and TE-related model parameters, and radiation quality metrics (relative biological effectiveness, RBE, and radiation effects ratio, RER, relative to γ rays) for each radiation type. Based on the modeled responses for each radiation type, we predicted the tumor yield for a Mars-mission-relevant mixture of these radiations, using the recently-developed incremental effect additivity (IEA) synergy theory. The proposed modeling approach can enhance current knowledge about quantification of space radiation quality effects, dose response shapes, and ultimately the health risks for astronauts.

DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1+/− mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs-/-/Ptch1+/− mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation.

PurposeTo date, only a few studies have examined long-term health risks of exposures in the uranium processing industry and reported contradictory results, necessitating further research in this area. This is the first description of a cohort of ∼65,000 uranium processing workers (20.6% women) of the Siberian Group of Chemical Enterprises (SGCE) in Seversk, Russia, first employed during 1950-2010.MethodsSGCE is one of the largest and oldest uranium processing complexes in the world. SGCE workers at the Radiochemical, Plutonium, Sublimate and Enrichment plants were exposed to a combination of internal and external radiation, while workers at the Support Facility were primarily exposed to non-radiation factors.ResultsMean cumulative gamma-ray dose based on individual external dosimetry was 28.3 millisievert. About 4,000 workers have individual biophysical survey data that could be used for estimation of organ doses from uranium. SGCE workers were followed up for mortality and cancer incidence during 1950-2013 (vital status known for 80.8% of workers). The SGCE computerized database contains information on the results of regular medical examinations, and on smoking, alcohol and other individual characteristics.ConclusionsThe SGCE cohort is uniquely suited to examine long-term health risks of exposures to gamma-radiation and long-lived radionuclides in uranium processing workers.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, andCLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.

The standard treatment for locally advanced cervical cancer (CC) is chemoradiotherapy. Once the bladder receives part of the radiation, a typical inflammatory condition that configures radiation-induced cystitis may develop. Chronic radiation-induced cystitis is commonly characterized by the bladder new submucosal vascularization, which is typically fragile and favors hematuria. The current study aims to investigate if Hypoxia-Induced Factor (HIF-1α) and its transcriptional target Vascular Endothelial Growth Factor A (VEGF-A) could be a primary pathway leading to increased submucosal vascularization. HIF-1α and VEGF-A mRNA levels in bladder core biopsies from CC patients treated with radiotherapy versus untreated (non-irradiated) patients were analyzed using a droplet digital polymerase chain reaction technology. Gene expression results showed that HIF-1α and VEGF-A had no significant differences between bladder samples from patients previously irradiated and untreated patient samples. However, a direct relationship between the degree of late morbidity and the expression of HIF-1α and VEGF-A has been demonstrated. Despite the lack of statistical significance precludes a definitive conclusion, the data presented herein suggests that further studies investigating the role of HIF-1α in bladder neovascularization in radiation-induced cystitis are highly recommended.

Purpose To study a robust and reproducible procedure to investigate a relation between focal brain radiotherapy (RT) low doses, neurocognitive impairment and late White Matter and Gray Matter alterations, as shown by Diffusion Tensor Imaging (DTI), in children. Methods and materials Forty-five patients (23 males and 22 females, median age at RT 6.2 years, median age at evaluations 11.1 years) who had received focal RT for brain tumors were recruited for DTI exams and neurocognitive tests. Patients’ brains were parceled in 116 regions of interest (ROIs) using an available segmented atlas. After the development of an ad hoc, home-made, multimodal and highly deformable registration framework, we collected mean RT doses and DTI metrics values for each ROI. The pattern of association between cognitive scores or domains and dose or DTI values was assessed in each ROI through both considering and excluding ROIs with mean doses higher than 75% of the prescription. Subsequently, a preliminary threshold value of dose discriminating patients with and without neurocognitive impairment was selected for the most relevant associations. Results The workflow allowed us to identify 10 ROIs where RT dose and DTI metrics were significantly associated with cognitive tests results (p Conclusion This analysis, despite being conducted on a retrospective cohort of children, shows that the identification of critical brain structures and respective radiation dose thresholds is achievable by combining, with appropriate methodological tools, the large amount of data arising from different sources. This supported the design of a prospective study to gain stronger evidence.

BackgroundThe study of Japanese atomic bomb survivors, exposed briefly to radiation, finds the risk of radiation-induced lung cancer to be nearly three times greater for women than for men. Because protection standards for astronauts are based on individual lifetime risk projections, this sex-specific difference limits the time women can spend in space. Populations exposed to chronic or fractionated radiation were evaluated to learn whether similar differences exist when exposures occur gradually over years.Methods and materialsFive occupational cohorts within the Million Person Study of Low-Dose Health Effects (MPS) and a Canadian Fluoroscopy Cohort Study (CFCS) of tuberculosis patients who underwent frequent chest fluoroscopic examinations are evaluated. Included are male and female workers at the Mound nuclear facility, nuclear power plants (NPP), and industrial radiographers (IR). Workers at the Mallinckrodt Chemical Works and military participants at aboveground nuclear weapons tests provide information on the risk among males. Cox proportional hazards and Poisson regression models were used to estimate sex-specific radiation risks for lung cancer and to compare any differences.ResultsOverall, 15,065 lung cancers occurred among the 443,684 subjects studied: 50,111 women and 395,573 men. The mean cumulative dose to the lung was 166.3 mGy (range 6 to 1,055 mGy) with the highest among the TB-fluoroscopy patients (mean 1,055 mGy). Mean lung dose for women in the worker cohorts was generally 4 times lower than for men. Of the 12 estimates of radiation-related risk, only one, for male IRs, showed a significant elevation (ERR 0.09; 95% CI 0.02-0.16, at 100 mGy). In contrast, the dose response for male NPP workers was negative (ERR -0.05; 95% CI -0.10, 0.01, at 100 mGy). Combined, these two cohorts provided little evidence for a radiation effect among males (ERR 0.01; 95% CI -0.04, 0.06, at 100 mGy). There was no significant dose-response among females within any cohort. There was no difference in the sex-specific estimates of lung cancer risk.ConclusionsThere was little evidence that chronic or fractionated exposures increased the risk of lung cancer. There were no differences in the risks of lung cancer between men and women. However, the sex-specific analyses are limited because of small numbers of women and relatively low doses. A more definitive study is ongoing of medical radiation workers which include 85,000 women and 85,000 men (overall mean dose 82 mGy, max 1,140 mGy). Additional understanding will come from the ongoing follow-up of the CFCS.

Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.

Advances in oncologic treatment have improved survival rates, allowing late effects of radiotherapy to become more prevalent. Our patient, an 82-year-old woman with a remote history of right thigh basal cell carcinoma treated with resection and radiation therapy 18 years prior, presented with severe right thigh pain and inability to bear weight as she had suffered a femur fracture after a fall from standing. Initial imaging was suspicious for pathologic fracture secondary to malignancy due to imaging findings and because radiation-induced fractures have rarely been reported beyond 44 months from treatment. However, upon further imaging, evidence pointed to radiation-induced osteonecrosis as the mechanism for her insufficiency fracture. This case highlights the permanent deleterious effects of radiation therapy on bone, and the prudence of considering radiation-induced osteonecrosis as a mechanism of injury in low-energy trauma even long after radiation therapy. In addition, the case serves to review the natural history of irradiated bone injury and pertinent imaging findings. Keywords: Radiotherapy, Musculoskeletal, Femur, Insufficiency, Fracture, Bone, Radiation-induced, Osteonecrosis

Summary Background Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (

Background: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association. Methods: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS. Results: We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08–1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83–2.43; P

To investigate the amount that radiation-induced secondary cancer would be reduced by using proton beam therapy (PBT) in place of intensity-modulated X-ray therapy (IMXT) in pediatric patients, we analyzed lifetime attributable risk (LAR) as an in silico surrogate marker of the secondary cancer after these treatments. From 242 pediatric patients with cancers who were treated with PBT, 26 patients were selected by random sampling after stratification into four categories: (i) brain, head and neck, (ii) thoracic, (iii) abdominal, and (iv) whole craniospinal (WCNS) irradiation. IMXT was replanned using the same computed tomography and region of interest. Using the dose–volume histograms (DVHs) of PBT and IMXT, the LARs of Schneider et al. were calculated for the same patient. All the published dose–response models were tested for the organs at risk. Calculation of the LARs of PBT and IMXT based on the DVHs was feasible for all patients. The means ± standard deviations of the cumulative LAR difference between PBT and IMXT for the four categories were (i) 1.02 ± 0.52% (n = 7, P = 0.0021), (ii) 23.3 ± 17.2% (n = 8, P = 0.0065), (iii) 16.6 ± 19.9% (n = 8, P = 0.0497) and (iv) 50.0 ± 21.1% (n = 3, P = 0.0274), respectively (one tailed t-test). The numbers needed to treat (NNT) were (i) 98.0, (ii) 4.3, (iii) 6.0 and (iv) 2.0 for WCNS, respectively. In pediatric patients who had undergone PBT, the LAR of PBT was significantly lower than the LAR of IMXT estimated by in silico modeling. Although a validation study is required, it is suggested that the LAR would be useful as an in silico surrogate marker of secondary cancer induced by different radiotherapy techniques.

Author(s): Cahoon, Elizabeth K; Nadyrov, Eldar A; Polyanskaya, Olga N; Yauseyenka, Vasilina V; Veyalkin, Ilya V; Yeudachkova, Tamara I; Maskvicheva, Tamara I; Minenko, Victor F; Liu, Wayne; Drozdovitch, Vladimir; Mabuchi, Kiyohiko; Little, Mark P; Zablotska, Lydia B; McConnell, Robert J; Hatch, Maureen; Peters, Kamau O; Rozhko, Alexander V; Brenner, Alina V | Abstract: ContextAlthough radiation exposure is an important predictor of thyroid cancer on diagnosis of a thyroid nodule, the relationship between childhood radiation exposure and thyroid nodules has not been comprehensively evaluated.ObjectiveTo examine the association between internal I-131 thyroid dose and thyroid nodules in young adults exposed during childhood.Design, setting, and participantsIn this cross-sectional study, we screened residents of Belarus aged ≤18 years at the time of the Chernobyl nuclear accident for thyroid disease (median age, 21 years) with thyroid palpation, ultrasonography, blood/urine analysis, and medical follow-up when appropriate. Eligible participants (N = 11,421) had intact thyroid glands and doses based on direct individual thyroid activity measurements.Main outcome measuresExcess odds ratios per Gray (EOR/Gy, scaled at age 5 years at exposure) for any thyroid nodule and for nodules grouped by cytology/histology, diameter size, and singularity.ResultsRisk of any thyroid nodule increased significantly with I-131 dose and, for a given dose, with younger age at exposure. The EOR/Gy (95% confidence intervals) for neoplastic nodules (3.82; 0.87 to 15.52) was significantly higher than for nonneoplastic nodules (0.32; l0.03 to 0.70) and did not vary by size; whereas the EOR/Gy for nonneoplastic nodules did vary by size (P = 0.02) and was 1.55 (0.36 to 5.46) for nodules ≥10 mm and 0.02 (l-0.02 to 0.70) for nodules l10 mm. EORs/Gy for single and multiple nodules were comparable.ConclusionsChildhood exposure to internal I-131 is associated with increased risk of neoplastic thyroid nodules of any size and nonneoplastic nodules ≥10 mm.

INTRODUCTION: As a result of the increased use of radiotherapy (RT) and improved long-term overall survival of patients with cancers of the head and neck (HN), the frequency of radiation-induced sarcomas of the head and neck (RISHN) may be increasing. The main objective of this systematic review was to determine the existing evidence on the frequency, treatment, and outcome of RISHN. METHODS: Using PRISMA guidelines we conducted a systematic review of the literature published from 2000 to 2020. RESULTS: Our review includes data of 560 patients from 64 articles. The total frequency of RISHNs among the reviewed series was 0.15%. The most frequent location of the primary tumor treated by RT was the nasopharynx. The mean RT dose used was 62 Gy, mean latency interval between irradiation and occurrence of RISHN was 11.1 years, and the most common RISHN location was the sinonasal region. Osteosarcoma was the principal histology, followed by fibrosarcoma. Surgery was the most frequently applied treatment modality. Of all patients with RISHN, 40.7% died of this disease after a mean interval of 13.9 months. CONCLUSIONS: Notwithstanding the increased use of RT, the number of reported RISHNs has not increased substantially during the past two decades. Surgery with wide margins forms the best therapeutic option for these cases, but the outcome remains poor. ispartof: ADVANCES IN THERAPY vol:38 issue:1 pages:90-108 ispartof: location:United States status: published

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (56Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours., Mutational signatures induced by ionising radiation remain largely unexplored. Here in TP53 mutant mice, the authors characterise the genomic landscape of tumours induced by high- and low-energy radiation.

There is limited information on how indoor tanning promotes melanoma development. We investigated indoor tanning use in patients with melanomas in sun-exposed skin and studied the clinicopathological and molecular characteristics in relation to indoor tanning exposure. Patients from a multidisciplinary clinic for cutaneous cancers completed standardized questionnaires on risk factors for melanoma as a component of medical history at their initial consultations. For this study, we included patients from December 2013 to May 2015. The 114 patients who reported indoor tanning exposure were younger at diagnosis than the 222 patients who did not (51.5 vs 64.0 years, two-sided P < .001). BRAF V600E genotype was more prevalent in ever-users than in nonusers (42.9% vs 28.3%, two-sided P = .04) and higher in ever-users who initiated indoor tanning prior to age 25 years compared with age 25 years or older (62.2% vs 31.1%, two-sided P = .003). There were more melanomas in intermittently sun-exposed skin in ever-users than nonusers (65.7% vs 51.9%, respectively, two-sided P = .02). Our data suggest indoor tanning may promote melanomas that arise in skin with low-chronic sun-induced damage through BRAF V600E-mediated melanomagenesis.

It is well established that high radon exposures increase the risk of lung cancer mortality. The effects of low occupational exposures and the factors that confound and modify this risk are not clear and are needed to inform current radiation protection of miners. The risk of lung cancer mortality at low radon exposures (

Although the incidence of secondary malignancies due to stereotactic radiosurgery are known to be lower than that of conventional external beam radiation therapy, various instances of secondary malignancy have been reported. We present a rare case of secondary gliosarcoma following gamma knife radiosurgery (GKS) after treatment of glioblastoma. An 81-year-old man underwent navigation-guided biopsy for an incidentally found intra-axial brain tumor in the left temporal lobe. Pathological results demonstrated this was an IDH1 wild-type glioblastoma. Following pathological confirmation, the Stupp regimen was implemented and completed 8 months after the surgery. In a follow-up magnetic resonance imaging (MRI) scan performed 1 year after the surgery, a small residual nodule had increased in size. GKS was performed on this lesion. However, after GKS, the growth rate of the tumor rather accelerated. Based on MRI scans, the tumor significantly increased in size between GKS implementation and a follow-up scan performed at 9 months after GKS. An anterior temporal lobectomy was performed that included the removal of the tumor. Pathology reports confirmed the tumor was a gliosarcoma.

A nearly 80-year-old man with a history of radiotherapy (RT) and total laryngectomy for laryngeal cancer 25 years previously presented with a rapidly growing mass on the right side of his neck. A huge pseudoaneurysm (pseudoAN) was detected at the right carotid bifurcation, though angiography performed four years previously had shown total occlusion of the internal carotid artery. Stent-assisted coil embolization enabled aneurysm sac shrinkage. Clinicians must be aware that the stump of an arterial occlusion associated with RT can change into a pseudoAN over the long term and must provide follow-up in such cases.

When treating childhood acute lymphoblastic leukemia (ALL), secondary neoplasms are a significant long term problem. Radiation is generally accepted to be a major cause of the development of secondary neoplasms. Following treatment for ALL, a variety of secondary tumors, including brain tumors, hematologic malignancies, sarcomas, thyroid cancers, and skin cancers have been reported. However, oligodendroglioma as a secondary neoplasm is extremely rare. Herein we present a case of secondary oligodendroglioma occurring 13 years after the end of ALL treatment.

Background Recurrent radiation-induced osteosarcoma of the sternum following remote radiation therapy for breast cancer and sternal reconstruction. Case A 51-year-old woman presents with recurrent, radiation-induced sternal osteosarcoma 11 years after receiving both radiation therapy for breast cancer and sternal reconstruction. The case details both her work-up and subsequent course, including reconstructive and curative efforts. Discussion An uncommon side effect of radiation therapy for breast cancer is development of osteosarcoma of the chest wall. Even rarer is recurrence of the osteosarcoma following sternal reconstruction.

Potential ionising radiation exposure scenarios are varied, but all bring risks beyond the simple issues of short-term survival. Whether accidentally exposed to a single, whole-body dose in an act of terrorism or purposefully exposed to fractionated doses as part of a therapeutic regimen, radiation exposure carries the consequence of elevated cancer risk. The long-term impact of both intentional and unintentional exposure could potentially be mitigated by treatments specifically developed to limit the mutations and precancerous replication that ensue in the wake of irradiation The development of such agents would undoubtedly require a substantial degree of in vitro testing, but in order to accurately recapitulate the complex process of radiation-induced carcinogenesis, well-understood animal models are necessary. Inbred strains of the laboratory mouse, Mus musculus, present the most logical choice due to the high number of molecular and physiological similarities they share with humans. Their small size, high rate of breeding and fully sequenced genome further increase its value for use in cancer research. This chapter will review relevant m. musculus inbred and F1 hybrid animals of radiation-induced myeloid leukemia, thymic lymphoma, breast and lung cancers. Method of cancer induction and associated molecular pathologies will also be described for each model.

BackgroundWhile an increased risk of thyroid cancer from post-Chernobyl exposure to Iodine-131 (I-131) in children and adolescents has been well-documented, risks of other cancers or leukemia as a result of residence in radioactively contaminated areas remain uncertain.MethodsWe studied non-thyroid cancer incidence in a cohort of about 12,000 individuals from Belarus exposed under age of 18 years to Chernobyl fallout (median age at the time of Chernobyl accident of 7.9 years). During 15 years of follow-up from1997 through 2011, 54 incident cancers excluding thyroid were identified in the study cohort with 142,968 person-years at risk. We performed Standardized Incidence Ratio (SIR) analysis of all solid cancers excluding thyroid (n=42), of leukemia (n=6) and of lymphoma (n=6).ResultsWe found no significant increase in the incidence of non-thyroid solid cancer (SIR=0.83, 95% Confidence Interval [CI]: 0.61; 1.11), lymphoma (SIR=0.66, 95% CI: 0.26; 1.33) or leukemia (SIR=1.78, 95% CI: 0.71; 3.61) in the study cohort as compared with the sex-, age- and calendar-time-specific national rates. These findings may in part reflect the relatively young age of study subjects (median attained age of 33.4 years), and long latency for some radiation-related solid cancers.ConclusionsWe found no evidence of statistically significant increases in solid cancer, lymphoma and leukemia incidence 25 years after childhood exposure in the study cohort; however, it is important to continue follow-up non-thyroid cancers in individuals exposed to low-level radiation at radiosensitive ages.

Background Long-term survival can be achieved in patients affected by localized prostate cancer (PCa) treated with either radical prostatectomy (RP) or external beam radiotherapy (EBRT). However, development of a second primary tumor is still poorly investigated. Objective To investigate the impact of RP and EBRT on subsequent risk of developing bladder (BCa) and/or rectal cancer (RCa) among PCa survivors. Design, setting, and participants A total of 84397 patients diagnosed with localized PCa, treated with RP or EBRT between 1988 and 2009, and older than 65 yr of age were identified in the Surveillance, Epidemiology, and End Results Medicare insurance program-linked database. Our primary objective was to investigate the effect of EBRT and RP on the second primary BCa and RCa incidence. Outcome measurements and statistical analysis Multivariable competing-risk regression analyses were performed to assess the risk of developing a second primary BCa or RCa. Results and limitations Of the 84397 individuals included in the study, 33252 (39%) were treated with RP and 51145 (61%) with EBRT. Median follow-up was 69 months, and follow-up periods for patients who did not develop BCa, RCa, or pelvic cancer were 68, 69, and 68 mo, respectively. A total of 1660 individuals developed pelvic tumors (1236 BCa and 432 RCa). The 5- and 10-yr cumulative BCa incidence rates were 0.75% (95% confidence interval [CI]: 0.64–0.85%) and 1.63% (95% CI: 1.45–1.80%) versus 1.26% (95% CI: 1.15–1.37%) and 2.34% (95% CI: 2.16–2.53%) for patients treated with RP versus EBRT, respectively. The 5- and 10-yr cumulative RCa incidence rates were 0.32% (95% CI: 0.25–0.39%) and 0.73% (95% CI: 0.61–0.85%) versus 0.36% (95% CI: 0.30–0.41%) and 0.69% (95% CI: 0.60–0.79%) for patients treated with RP versus EBRT, respectively. On multivariable competing risk regression analyses, treatment with EBRT was independently associated with the risk of developing a second primary BCa (hazard ratio: 1.35, CI: 1.18–1.55; p Conclusions Patients treated with EBRT are at increased risk of developing a second primary BCa compared with those treated with RP. However, no differences were found considering RCa incidence in patients treated with RP or EBRT within the first 5 yr after primary therapy. These results need to be validated in a well-designed randomized prospective trial. Patient summary We retrospectively analyzed the risk of developing a second primary bladder or rectal cancer during follow-up for patients treated with radical prostatectomy or external beam radiotherapy for a localized prostate cancer. We found that those treated with external beam radiotherapy are at an increased risk of developing a second primary bladder cancer tumor.

International audience; Purpose Stereotactic body radiation therapy offers good lung local tumor control by the administration of a high dose per fraction in small volumes. Stereotactic body radiation therapy preclinical modeling is now possible, and our aim was to develop a model of focal irradiation of the mouse lung and to investigate the impact of conditional hypoxia-inducible factor 1α (HIF-1α) deletion in the endothelium on radiation-induced tissue damage. Methods and Materials The Small Animal Radiation Research Platform was used to create a mouse model of focal irradiation of the lung using arc therapy. HIF-1α conditional deletion was obtained by crossing mice expressing Cre recombinase under the endothelial promoter VE-cadherin (VECad-Cre +/+ mice) with HIF-1α floxed mice. Results Lung stereotactic arc therapy allows thoracic wall sparing and long-term studies. However, isodose curves showed that neighboring organs received significant doses of radiation, as revealed by ipsilateral lung acute red hepatization and major gene expression level modifications. Conditional HIF-1α deletion reduced acute lung edema and tended to diminish neutrophil infiltrate, but it had no impact on long-term global tissue damage. Conclusions Arc therapy for focal high-dose irradiation of mouse lung is an efficient model for long-term studies. However, irradiation may have a strong impact on the structure and function of neighboring organs, which must be considered. HIF-1α conditional deletion has no beneficial impact on lung damage in this irradiation schedule. © 2019

In the last decades, radiotherapy (RT) has become one of the cornerstones in the treatment of head and neck (HN) malignancies and has paralleled an increase in long-term patient survival. This lead to a concomitant increase in the incidence of radiation-induced sarcomas (RIS) of the irradiated field, with an annual rate up to 0.17%. The new techniques of irradiation do not seem to influence the risk of RIS of the HN (RISHN), which mainly develop within the middle-dose field. The median latency of RISHN after RT is 10–12 years and osteosarcoma is the most represented histotype, even though there is a high variability in time of occurrence and histological features observed. There is no clear evidence of predisposing factors for RISHN, and genetic findings so far have not revealed any common mutation. Early clinical diagnosis of RISHN is challenging, since it usually occurs within fibrotic and hardened tissues, while radiological findings are not pathognomonic and able to differentiate them from other neoplastic entities. Given the highly aggressive behavior of RISHN and its poor sensitivity to chemotherapy, radical surgery is the most important prognostic factor and the only curative option at present. Nevertheless, the anatomy of the HN district and the infiltrative nature of RIS do not always allow radical intervention. Therefore, a wise integration with systemic therapy and, when feasible, re-irradiation should be performed. Future findings in the genomic features of RISHN will be crucial to identify a possible sensitivity to specific drugs in order to optimize a multimodal treatment that will be ideally complementary to surgery and re-irradiation.

Astronauts traveling in deep space are exposed to high-charge and energy (HZE) particles from galactic cosmic rays. We have previously determined that irradiation of adult female mice with iron HZE particles induces DNA double-strand breaks, oxidative damage and apoptosis in ovarian follicles, causing premature ovarian failure. These effects occur at lower doses than with conventional photon irradiation. Ovarian failure with resultant loss of negative feedback and elevated levels of gonadotropin hormones is thought to play a role in the pathophysiology of ovarian cancer. Therefore, we hypothesized that charged-iron-particle irradiation induces ovarian tumorigenesis in mice. In this study, three-month-old female mice were exposed to 0 cGy (sham) or 50 cGy iron ions and aged to 18 months. The 50 cGy irradiated mice had increased weight gain with age and lack of estrous cycling, consistent with ovarian failure. A total of 47% and 7% of mice irradiated with 50 cGy had unilateral and bilateral ovarian tumors, respectively, whereas 14% of mice in the 0 cGy group had unilateral tumors. The tumors contained multiple tubular structures, which were lined with cells positive for the epithelial marker cytokeratin, and had few proliferating cells. In some tumors, packets of cells between the tubular structures were immunopositive for the granulosa cell marker FOXL2. Based on these findings, tumors were diagnosed as tubular adenomas or mixed tubular adenoma/granulosa cell tumors. In conclusion, charged-iron-particle-radiation induces ovarian tumors in mice, raising concerns about ovarian tumors as late sequelae of deep space travel in female astronauts.

Background Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. Methods A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). Results Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p

SummaryIonizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape.

Radiotherapy is the main treatment modality for nasopharyngeal carcinoma. However, ionizing radiation is itself a known carcinogen, and sarcomas can be a complication of treatment. Radiation-induced osteosarcomas in the head and neck are particular rare. Imaging studies of radiation-induced sarcomas in patients with head and neck carcinoma have been limited to case reports and relatively small case series. We report an unusual case of a radiation-induced osteosarcoma of the mandibular ramus following radiotherapy for nasopharyngeal carcinoma with computed tomography (CT) and magnetic resonance imaging (MRI). These findings can be helpful for differentiating osteosarcoma from other tumors of the mandible.

A rare case of trichilemmal carcinoma in a 40-year-young female is reported. She presented with a horny ulcerated lesion over anterior aspect of left arm. Strong history of exposure to sun, which is the main contributory factor for its aetiopathogenesis is present. Patient underwent wide surgical excision and diagnosis was established on histopathological examination with positive surgical margins. Hence adjuvant radical radiotherapy was administered. She is now on disease free followup for last 4 years.

Purpose Long-term health risks of occupational exposures to uranium processing were examined to better understand potential differences with uranium underground miners and nuclear reactor workers. Methods A cohort study of mortality of workers from Port Hope, Canada (1950–1999) and Wismut, Germany (1946–2008) employed in uranium milling, refining, and processing was conducted. Poisson regression was used to evaluate the association between cumulative exposures to radon decay products (RDP) and gamma-rays and causes of death potentially related to uranium processing. Results The pooled cohort included 7431 workers (270,201 person-years of follow-up). Mean RDP exposures were lower than in miners while gamma-ray doses were higher than in reactor workers. Both exposures were highly correlated (weighted rho = 0.81). Radiation risks of lung cancer and cardiovascular diseases (CVD) in males were increased but not statistically significant and compatible with risks estimated for miners and reactor workers, respectively. Higher RDP-associated CVD risks were observed for exposures 5–14 years prior to diagnosis compared to later exposures and among those employed

Item does not contain fulltext BACKGROUND: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. METHODS: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports. RESULTS: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause /=50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P/=2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. CONCLUSIONS: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.

We report a case of a long-term local control and survival achieved in a patient affected by radiation-induced angiosarcoma (RIA). A 57-year-old woman had a history of breast-conserving surgery and radiation therapy for primary breast cancer. Eight years after the mastectomy, multiple nodal progression was diagnosed as RIA and subsequentially treated by salvage lymph node dissection followed by adjuvant intensified radiotherapy to control the residual disease. Two and a half years later, the patient is alive and cancer-free. This experience shows that radiotherapy may have the potential to be a feasible and effective treatment to control RIA progression, and it may also play a role in the management of RIA as adjuvant.

The recently demonstrated radiation-induction of chronic lymphocytic leukemia (CLL) raises the question as to whether the amount of radiation exposure influences any of the clinical characteristics of the disease. We evaluated the relationship between bone marrow radiation doses and clinical characteristics and survival of 79 CLL cases diagnosed during 1986-2006 in a cohort of 110 645 male workers who participated in the cleanup work of the Chornobyl nuclear accident in Ukraine in 1986. All diagnoses were confirmed by an independent International Hematology Panel. Patients were followed up to the date of death or end of follow-up on 31 October 2010. The median age at diagnosis was 57 years. Median bone marrow dose was 22.6 milligray (mGy) and was not associated with time between exposure and clinical diagnosis of CLL (latent period), age, peripheral blood lymphocyte count or clinical stage of disease in univariate and multivariate analyses. Latent period was significantly shorter among those older at first exposure, smokers and those with higher frequency of visits to the doctor prior to diagnosis. A significant increase in the risk of death with increasing radiation dose was observed (p = 0.03, hazard ratio = 2.38, 95% confidence interval: 1.11,5.08 comparing those with doses ≥22 mGy to doses

Ultra violet (UV) irradiation, in particular UVB, is the single most important carcinogen for skin tumor formation. UVB induces genetic mutations and immune suppression, which lead to abnormal cell proliferation and eventually tumor formation. Previously studies from our group and others demonstrated that both global and epidermal specific VDR knock out mice are predisposed to either chemical (DMBA)- or long-term UVB-induced skin tumor formation, paralleled by an increase in β-catenin signaling. Using primary cultured human keratinocytes, we further demonstrated that 1,25(OH)2-dihydroxyvitamin D3 (1,25(OH)2D3) suppresses cyclin D1 and Gli1 which are regulated by β-catenin/TCF signaling and have a critical role in epidermal carcinogenesis. Blockage of VDR by siRNA resulted in hyperproliferation of keratinocytes, and increased expression of cyclin D1 and Gli1. In addition, we also showed that 1,25(OH)2D3/VDR directly regulates transcriptional activity of β-catenin/TCF signaling using the -catenin reporter TopGlow. Using K14 driven tamoxifen-induced cre recombinase to delete both VDR and β-catenin in keratinocytes of mice following the first hair follicle cycle, we found that ablation of epidermal specific β-catenin cannot rescue VDR null mice from UVB-induced skin tumor formation. Further study using VDR or β-catenin single null mice is necessary to compare with the data from double null mice. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

International audience; The meeting held in May 2014 in Würzburg, Germany, discussed the scope of the revision of the 1999 WHO guidelines for iodine thyroid blocking (ITB) by following the WHO handbook for guideline development. This article describes the process and methods of developing the revised, evidence-based WHO guidelines for ITB following nuclear and radiological accidents, the results of the kick-off meeting as well as further steps taken to complete the revision. © World Health Organisation 2016. All rights reserved.

It has been 30 years since the worst accident in the history of the nuclear era occurred at the Chernobyl power plant in Ukraine close to densely populated urban areas. To date, epidemiological studies reported increased long-term risks of leukemia, cardiovascular diseases, and cataracts among cleanup workers and of thyroid cancer and non-malignant diseases in those exposed as children and adolescents. Mental health effects were the most significant public health consequence of the accident in the three most contaminated countries of Ukraine, Belarus, and the Russian Federation. Timely and clear communication with affected populations emerged as one of the main lessons in the aftermath of the Chernobyl nuclear accident.

The Janus series of radiation experiments, conducted from 1970 to 1992, explored the effects of gamma and neutron radiation on animal lifespan and disease development. Data from these experiments presents an opportunity to conduct a large scale analysis of both tumor and non-tumor disease development. This work was focused on a subset of animals from the Janus series of experiments, comparing acute or fractionated exposures of gamma or neutron radiation on the hazards associated with the development of tumor and non-tumor diseases of the liver, lung, kidney or vascular system. This study also examines how the co-occurrence of non-tumor diseases may affect tumor-associated hazards. While exposure to radiation increases the hazard of dying with tumor and non-tumor diseases, dose fractionation modulates these hazards, which varies across different organ systems. Finally, the effect that concurrent non-cancer diseases have on the hazard of dying with a tumor also differs by organ system. These results highlight the complexity in the effects of radiation on the liver, lung, kidney and vascular system.

The aim of the present paper is to compare the integral dose received by non-tumor tissue (NTID) in stereotactic body radiation therapy (SBRT) with modified LINAC with that received by three-dimensional conformal radiotherapy (3D-CRT), estimating possible correlations between NTID and radiation-induced secondary malignancy risk. Eight patients with intrathoracic lesions were treated with SBRT, 23 Gy × 1 fraction. All patients were then replanned for 3D-CRT, maintaining the same target coverage and applying a dose scheme of 2 Gy × 32 fractions. The dose equivalence between the different treatment modalities was achieved assuming α/β = 10Gy for tumor tissue and imposing the same biological effective dose (BED) on the target (BED = 76Gy10). Total NTIDs for both techniques was calculated considering α/β = 3Gy for healthy tissue. Excess absolute cancer risk (EAR) was calculated for various organs using a mechanistic model that includes fractionation effects. A paired two-tailed Student t-test was performed to determine statistically significant differences between the data (p ≤ 0.05). Our study indicates that despite the fact that for all patients integral dose is higher for SBRT treatments than 3D-CRT (p = 0.002), secondary cancer risk associated to SBRT patients is significantly smaller than that calculated for 3D-CRT (p = 0.001). This suggests that integral dose is not a good estimator for quantifying cancer induction. Indeed, for the model and parameters used, hypofractionated radiotherapy has the potential for secondary cancer reduction. The development of reliable secondary cancer risk models seems to be a key issue in fractionated radiotherapy. Further assessments of integral doses received with 3D-CRT and other special techniques are also strongly encouraged.

Secondary bone tumours arising in the field of a preceding radiotherapy are a serious late effect, in particular considering the increasing survival times in patients treated for paediatric malignancies. In general, therapy associated tumours are known to show a more aggressive behaviour and a limited response to chemotherapy compared with their primary counterparts. It is not clear however whether this less favourable outcome is caused by inherent genetic factors of the tumour cells or by a general systemic condition of the patient. To elucidate this we analysed a series of bone sarcomas with a history of prior irradiation for the presence of genomic alterations and compared them with the alterations identified earlier in primary osteosarcomas. We analysed seven radiation induced bone sarcomas for genome-wide losses of heterozygosity (LOH) using Affymetrix 10K2 high-density single nucleotide polymorphism (SNP) arrays. Additionally, copy number changes were analysed at two distinct loci on 10q that were recently found to be of major prognostic significance in primary osteosarcomas. All the investigated tumours showed a LOH at 10q21.1 with 86% of cases (6/7) revealing a total genome-wide LOH score above 2400 and more than 24% of the genome being affected. Our results indicate similar genetic alterations in radiation induced sarcomas of bone and primary osteosarcomas with a poor prognosis. We speculate that the high degree of genomic instability found in these tumours causes the poor prognosis irrespective of the initiating event.

Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165 pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously been investigated. Mutation analysis was performed by use of pyrosequencing and, additionally, data were validated for a cohort of 70 gliomas from among the series by use of the arrayed primer extension technique. We identified one tumor which harbored mutation of IDH1 at codon 132 and no alteration was identified in the matched-germline DNA. No IDH2 mutations were detected. Most noteworthy, the IDH1 mutant tumor was an anaplastic astrocytoma involving the cortex in the left frontal lobe which appeared seven years after radiation treatment for an extensive sellar/suprasellar craniopharyngioma. This anaplastic astrocytoma was regarded as secondary to radiation treatment because it seemed to originate within the irradiation field that received a dose varying from a maximum of 30.6 Gy of 4 MV X-rays down to very few Gy of lower-energy scattered radiation. In this work our observations agree with those in previous reports showing the rarity of IDH1/2 mutations in childhood tumors. The interesting identification of an IDH1 mutation in a radiation-induced secondary malignant glioma raises the likelihood that these types of tumor may develop IDH1/2 mutations. Thus, caution is needed when dealing with these tumors, and further genetic analysis is warranted.

Background: This study aims to provide reasons for the poor sarcoma-related survival in patients with radiation-induced sarcoma (RIS). Methods: We performed a case–control study comparing sarcoma-related survival of 98 patients with RIS to that of 239 sporadic high-grade malignant sarcomas. Results: The cumulative sarcoma-related 5-year survival was 32% (95% confidence interval (CI): 22–42) for patients with RIS vs 51% (95% CI: 44–58) for controls (P

A genome-wide screen for genetic alterations in radiation-induced thymic lymphomas generated from p53 +-and p53-/-mice showed frequent loss of heterozygosity (LOH) on chromosome 6. Fine mapping of these LOH regions revealed three non-overlapping regions, one of which was refined to a 0.2 Mb interval that contained only the gene encoding homeobox-interacting protein kinase 2 (Hipk2). More than 30% of radiation-induced tumors from both p53 +-and p53-/-mice showed heterozygous loss of one Hipk2 allele. Mice carrying a single inactive allele of Hipk2 in the germline were susceptible to induction of tumors by γ-radiation, but most tumors retained and expressed the wild-type allele, suggesting that Hipk2 is a haploinsufficient tumor suppressor gene for mouse lymphoma development. Heterozygous loss of both Hipk2 and p53 confers strong sensitization to radiation-induced lymphoma. We conclude that Hipk2 is a haploinsufficient lymphoma suppressor gene. © 2012 Macmillan Publishers Limited All rights reserved.

Recent advances in radiotherapy have enabled the use of different types of particles, such as protons and heavy ions, as well as refinements to the treatment of tumours with standard sources (photons). However, the risk of second cancers arising in long-term survivors continues to be a problem. The long-term risks from treatments such as particle therapy have not yet been determined and are unlikely to become apparent for many years. Therefore, there is a need to develop risk assessments based on our current knowledge of radiation-induced carcinogenesis.

The association between ionizing radiation and the subsequent development of osteosarcoma has been well described, but little is known about the cytogenetic and molecular events, which could be involved in the formation of radiation-induced osteosarcomas. Here, we performed comparative genomic hybridization (CGH) to detect chromosomal copy number changes in a series of 16 rat osteosarcomas induced by injection of plutonium-238. Recurrent gains/amplifications were observed at chromosomal regions 3p12-q12, 3q41-qter, 4q41-qter, 6q12-q16, 7q22-q34, 8q11-q23, 9q11-q22, 10q32.1-qter, and 12q, whereas recurrent losses were observed at 1p, 1q, 3q23-q35, 5q21-q33, 8q24-q31, 10q22-q25, 15p, 15q, and 18q. The gained region at 7q22-q34 was homologous to human chromosome bands 12q13-q15/8q24/22q11-q13, including the loci of Mdm2, Cdk4, c-Myc and Pdgf-b genes. The lost regions at 5q21-q33, 10q22-q25 and 15q contained tumor suppressor genes such as p16INK4a/p19ARF, Tp53 and Rb1. To identify potential target gene(s) for the chromosomal aberrations, we compared the expression levels of several candidate genes, located within the regions of frequent chromosomal aberrations, between the tumors and normal osteoblasts by using quantitative RT-PCR analysis. The Cdk4, c-Myc, Pdgf-b and p57KIP2 genes were thought to be possible target genes for the frequent chromosomal gain at 7q22-34 and loss at 1q in the tumors, respectively. In addition, mutations of the Tp53 gene were found in 27% (4 of 15) osteosarcomas. Our data may contribute to further understanding of the molecular mechanisms underlying osteosarcomas induced by ionizing radiation in human.

Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of 222Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations living in high natural background radiation (HNBR) areas (Guarapari, Brazil; Kerala, India; Ramsar, Iran; Yangjiang, China), including radon-prone areas, to low dose risk estimation. Much of the direct information about risk related to HNBR comes from case-control studies of radon and lung cancer, which provide convincing evidence of an association between long-term protracted radiation exposures in the general population and disease incidence. The success of these studies is mainly due to the careful organ dose reconstruction (with relatively high doses to the lung), and to the fact that large-scale collaborative studies have been conducted to maximise the statistical power and to ensure the systematic collection of information on potential confounding factors. In contrast, studies in other (non-radon) HNBR areas have provided little information, relying mainly on ecological designs and very rough effective dose categorisations. Recent steps taken in China and India to establish cohorts for follow-up and to conduct nested case-control studies may provide useful information about risks in the future, provided that careful organ dose reconstruction is possible and information is collected on potential confounding factors. © 2009 IOP Publishing Ltd.