Association between radiation therapy for primary endometrial cancer and risk of second primary malignancies: a retrospective cohort study.

Our objective was to evaluate the association of adjuvant radiation therapy (RT) to subsequent second primary malignancies (SPMs) in endometrial cancer survivors. Patients with endometrial cancer as their first malignancy were identified from 8 registries of the Surveillance, Epidemiology, and End Results (SEER) database. SPMs were defined as any type of primary malignancy that occurred more than 12 months after the diagnosis of endometrial cancer. Fine-Gray competing risk regression and Poisson regression were used to evaluate the radiotherapy-associated risk (RR) for SPMs. The Kaplan-Meier method was applied to assess the survival outcomes of endometrial cancer patients. Of 62,108 endometrial cancer patients,16,846 patients (27.12%) were in the RT group, and 45,262 patients (72.88%) were in the no-RT group. During the 30-year follow-up period, the cumulative incidence of SPMs was 20.9% and 19.7% in each group, respectively. In both multivariable competing risk regression analysis and Poisson regression analysis, adjuvant RT was found to be associated with a higher risk of developing colon and rectum cancer (adjusted hazard ratio (HR), 1.29; 95% confidence interval (CI), 1.12-1.50; P < 0.001; adjusted RR, 1.29; 95% CI, 1.11-1.49; P < 0.001), lung and bronchus cancer (adjusted HR, 1.27; 95% CI, 1.08-1.50; P = 0.004; adjusted RR, 1.26; 95% CI, 1.07-1.49; P = 0.005), vulva cancer (adjusted HR, 1.72; 95% CI, 1.04-2.85; P = 0.036; adjusted RR, 1.74; 95% CI, 1.03-2.88; P = 0.035), urinary bladder cancer (adjusted HR, 1.86; 95% CI, 1.41-2.46; P < 0.001; adjusted RR, 1.85; 95% CI, 1.40-2.44; P < 0.001), and non-Hodgkin lymphoma (adjusted HR, 1.37; 95% CI, 1.06-1.77; P = 0.016; adjusted RR, 1.37; 95% CI, 1.05-1.76; P = 0.017). However, a slightly decreased risk of breast cancer was observed in patients who underwent adjuvant RT (adjusted HR, 0.89; 95% CI, 0.80-0.98; P = 0.021; adjusted RR, 0.88; 95% CI, 0.80-0.98; P = 0.020). The RR for colon and rectum cancer decreased with age and elevated with increasing latency since endometrial cancer diagnosis, and the RR for urinary bladder cancer showed a similar tendency with latency. SPMs can significantly impair the survival outcomes of primary endometrial cancer survivors. Our findings suggest that adjuvant RT for endometrial cancer patients increases the risk of non-Hodgkin lymphoma and several types of solid cancer. Long-term surveillance of these patients should be recommended for detecting SPMs.

Healthy worker hire and survivor effects in a cohort of medical radiation workers.

BACKGROUND: The healthy worker effect may distort the association between exposure and health effects in workers. However, few studies have investigated both the healthy worker hire and survival effects simultaneously, and they are limited to mortality studies in male workers. METHODS: We utilized a data set comprising South Korean diagnostic medical radiation workers registered in the National Dose Registry between 1996 and 2011, and merged it with mortality and cancer incidence data. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were computed for comparison with the general population. To account for time-varying confounders influenced by prior occupational radiation exposure, we applied g-estimation using structural nested accelerated failure time models and compared the outcomes with those from Weibull regression. RESULTS: A total of 1831 deaths and 3759 first primary cancer cases were identified among 93 918 workers. Both male (SMR = 0.44; 95% CI: 0.42, 0.46) and female workers (SMR = 0.53; 95% CI: 0.46, 0.60) showed lower mortality rates compared with national rates. In the SIR analysis, male workers exhibited reduced risks of solid cancer whereas female workers had increased risks. The g-estimation-derived hazard ratios (HRs) from radiation exposure exceeded those from Weibull regression estimates for all-cause death (HR = 2.55; 95% CI: 1.97, 3.23) and all-cancer incidence (HR = 1.96; 95% CI: 1.52, 2.55) in male workers whereas female workers showed the opposite results. CONCLUSIONS: Comprehensive consideration of the healthy worker effect by sex is essential for estimating the unbiased impact of occupational exposure on health outcomes, notably in studies focusing on male mortality.

Proton beam therapy in a patient with secondary glioblastoma (32 years after postoperative irradiation of medulloblastoma): case report and literature review.

OBJECTIVE: This report details the experience of a patient who developed a second primary glioblastoma (GB), offering insights into the treatment process and reviewing relevant literature. CASE PRESENTATION: A male patient, who was diagnosed with medulloblastoma at age 9, received treatment with cobalt-60 craniospinal irradiation (CSI) (36 Gy/20 fractions) and a tumor bed boost (total of 56 Gy). After 32 years, at age 41, an MRI revealed a space-occupying mass in the left cerebellar hemisphere. Surgical resection was performed, and postoperative pathology confirmed a diagnosis of radiation-induced glioblastoma (RIGB). Given the history of irradiation and the current tolerability of brainstem doses, proton beam therapy (PBT) combined with Temozolomide (75 mg/m2) was chosen. The treatment plan included 60 Gy on the gross tumor bed and 54 Gy on the clinical target volume, delivered in 30 fractions. The patient underwent regular follow-up and achieved a complete response. CLINICAL DISCUSSION: For childhood cancer survivors, the development of a second primary tumor significantly impacts prognosis. RIGB is a rare form of secondary tumor with distinct molecular characteristics compared to primary GB and recurrent secondary GB. Molecular markers such as IDH and MGMT status can help differentiate between primary GB, recurrent secondary GB, and radiation-induced secondary GB in patients with a history of prior radiation therapy. Surgical resection remains a primary treatment option, while PBT is preferred for postoperative treatment due to its superior protection of normal tissues and the ability to deliver high-dose irradiation. CONCLUSION: RIGB is a rare second primary tumor that requires strategic molecular profiling and individualized management. Proton beam therapy provides effective high-dose irradiation in the postoperative phase and is the preferred treatment option for such cases.

AB051. Multiple meningiomas developed outside the radiation field after cranial irradiation: a case report.

BACKGROUND: Cranial irradiation has well-known long-term side effects, including radiation-induced neoplasms and vasculopathy. This report describes a case of aggressive and rapid-growing multiple meningiomas developed outside the radiation field after the treatment of medulloblastoma. CASE DESCRIPTION: A 6-year-old boy underwent surgery (gross total resection) and radiotherapy (19.8 Gy for posterior fossa only) against medulloblastoma in the 4th ventricle. The patient could not receive further craniospinal irradiation because of ventriculoperitoneal shunt-related complications. Eighteen years after the radiotherapy, the first meningioma developed in the right temporal convexity, without recurrence of medulloblastoma. It was left untreated because it was asymptomatic. Three years later, the meningioma grew from 0.6 to 6.3 cm3 in volume and another large meningioma (22.1 cm3) developed in the left temporal convexity with additional small meningioma in the right frontal convexity. The left large temporal meningioma showed aggressive nature invading the adjacent temporal bone and temporalis muscle. It was completely resected and the histology revealed as transitional meningioma with 2% of Ki-67. Another new meningioma was identified on the right cerebellar convexity three years post-craniotomy. Subsequent follow-up indicated a progressive increase in the tumor size and gamma knife radiosurgery was performed with right frontal convexity small meningioma. The patient is currently under ongoing surveillance through follow-up assessments. CONCLUSIONS: For patients who received radiotherapy at a young age, clinicians should consider the possibility of secondary neoplasm development even outside the radiation field. Careful imaging follow-up and surgical management are warranted because of the aggressive nature of secondary tumors even though benign in histology.

Changes in mouse epidermal DNA methylation during development of squamous cell carcinoma in response to UVR.

Squamous cell carcinoma (SCC) is a common skin cancer, often caused by exposure to ultraviolet radiation (UVR). Recent studies have shown that changes in DNA methylation play a crucial role in the development of cancers. However, methylation patterns of SCC are not well characterised. Identifying biomarkers for the risk of developing SCC could be helpful for early detection and diagnosis and can potentially improve treatment and prevention strategies. This study aimed to investigate methylation changes in the epidermis of mice exposed to UVR for 24 weeks. We examined the DNA methylation levels of 260 199 CpGs using the Illumina Infinium Mouse Methylation BeadChip and studied the epidermis of UVR-exposed and unexposed mice every 4 weeks for 24 weeks (n = 39). We identified CpGs with large differences in methylation levels (ß-values) between UVR-exposed and unexposed mice. We also observed differences in the epigenetic age of these mice. We identified CpGs in Rev, Ipmk, Rad51b, Fgfr2, Fgfr3 and Ctnnb1 that may serve as potential biomarkers for SCC risk and could be helpful for the early detection and prevention of SCC. Further investigations are necessary to determine the biological functions and clinical significance of these CpGs.

Radiation-Induced Childhood Thyroid Cancer after the Fukushima Daiichi Nuclear Power Plant Accident.

After the Fukushima Nuclear Power Plant accident in March 2011, a large-scale ultrasound examination of childhood thyroid cancer for all Fukushima residents aged 18 years old or younger was initiated. Fukushima was divided into four areas according to the external radioactivity released by the accident: the highest (A), high-intermediate (B), low-intermediate (C), and the lowest (D). Five rounds of surveys were carried out from October 2011 to March 2023. The annual incidence rates of the "Common Case" not affected by the accident were able to be estimated. The difference between the incidence rate of whole patients and the "Common Case" is that of the "Radiation-induced Case". The annual incidence rate of the "Radiation-induced Case" began to increase immediately after the accident, where the highest level was seen in A area, and the order was A > B > C > D. It showed that the development of childhood thyroid cancer was affected by the radiation released by the accident. The effect of the radiation consisted of two phases: the first phase may have been due to the damage to the immune system, and the second phase may have been due to the genetic mutation in the children who were youngest at the time of the accident.

Leukaemia, lymphoma, and multiple myeloma mortality after low-level exposure to ionising radiation in nuclear workers (INWORKS): updated findings from an international cohort study.

BACKGROUND: A major update to the International Nuclear Workers Study (INWORKS) was undertaken to strengthen understanding of associations between low-dose exposure to penetrating forms of ionising radiation and mortality. Here, we report on associations between radiation dose and mortality due to haematological malignancies. METHODS: We assembled a cohort of 309 932 radiation-monitored workers (269 487 [87%] males and 40 445 [13%] females) employed for at least 1 year by a nuclear facility in France (60 697 workers), the UK (147 872 workers), and the USA (101 363 workers). Workers were individually monitored for external radiation exposure and followed-up from Jan 1, 1944, to Dec 31, 2016, accruing 10·72 million person-years of follow-up. Radiation-mortality associations were quantified in terms of the excess relative rate (ERR) per Gy of radiation dose to red bone marrow for leukaemia excluding chronic lymphocytic leukaemia (CLL), as well as subtypes of leukaemia, myelodysplastic syndromes, non-Hodgkin and Hodgkin lymphomas, and multiple myeloma. Estimates of association were obtained using Poisson regression methods. FINDINGS: The association between cumulative dose to red bone marrow, lagged 2 years, and leukaemia (excluding CLL) mortality was well described by a linear model (ERR per Gy 2·68, 90% CI 1·13 to 4·55, n=771) and was not modified by neutron exposure, internal contamination monitoring status, or period of hire. Positive associations were also observed for chronic myeloid leukaemia (9·57, 4·00 to 17·91, n=122) and myelodysplastic syndromes alone (3·19, 0·35 to 7·33, n=163) or combined with acute myeloid leukaemia (1·55, 0·05 to 3·42, n=598). No significant association was observed for acute lymphoblastic leukaemia (4·25, -4·19 to 19·32, n=49) or CLL (0·20, -1·81 to 2·21, n=242). A positive association was observed between radiation dose and multiple myeloma (1·62, 0·06 to 3·64, n=527) whereas minimal evidence of association was observed between radiation dose and non-Hodgkin lymphoma (0·27, -0·61 to 1·39, n=1146) or Hodgkin lymphoma (0·60, -3·64 to 4·83, n=122) mortality. INTERPRETATION: This study reports a positive association between protracted low dose exposure to ionising radiation and mortality due to some haematological malignancies. Given the relatively low doses typically accrued by workers in this study (16 mGy average cumulative red bone marrow dose) the radiation attributable absolute risk of leukaemia mortality in this population is low (one excess death in 10 000 workers over a 35-year period). These results can inform radiation protection standards and will provide input for discussions on the radiation protection system. FUNDING: National Cancer Institute, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Institut de Radioprotection et de Sûreté Nucléaire, Orano, Electricité de France, UK Health Security Agency. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Development of Melanoma and Other Nonkeratinocyte Skin Cancers After Thyroid Cancer Radiation.

This cohort study evaluates the association between thyroid malignant neoplasms and melanoma and other nonkeratinocyte skin cancers.

Utilizing patient data: A tutorial on predicting second cancer with machine learning models.

BACKGROUND: The article explores the potential risk of secondary cancer (SC) due to radiation therapy (RT) and highlights the necessity for new modeling techniques to mitigate this risk. METHODS: By employing machine learning (ML) models, specifically decision trees, in the research process, a practical framework is established for forecasting the occurrence of SC using patient data. RESULTS & DISCUSSION: This framework aids in categorizing patients into high-risk or low-risk groups, thereby enabling personalized treatment plans and interventions. The paper also underscores the many factors that contribute to the likelihood of SC, such as radiation dosage, patient age, and genetic predisposition, while emphasizing the limitations of current models in encompassing all relevant parameters. These limitations arise from the non-linear dependencies between variables and the failure to consider factors such as genetics, hormones, lifestyle, radiation from secondary particles, and imaging dosage. To instruct and assess ML models for predicting the occurrence of SC based on patient data, the paper utilizes a dataset consisting of instances and attributes. CONCLUSION: The practical implications of this research lie in enhancing our understanding and prediction of SC following RT, facilitating personalized treatment approaches, and establishing a framework for leveraging patient data within the realm of ML models.

The National Cancer Aid monitoring (NCAM-online) of ultraviolet radiation risk and protection behavior: a population-based observational trend study with four annual online survey waves.

BACKGROUND: Ultraviolet (UV) radiation is the most important risk factor for skin cancer development. Sunlight is the main source of UV radiation in the general population. In addition, tanning beds are a source of artificial UV radiation. Since the incidence of skin cancer is increasing worldwide, it is necessary to monitor UV-related risk behaviors such as intentional indoor and outdoor tanning, as well as sun protection behavior in the general population and specific subgroups and settings. This is the aim of the National Cancer Aid Monitoring online (NCAM-online), a continuation and further development of the NCAM. METHODS: The NCAM-online is a longitudinal trend study consisting of four annual survey waves. Each year, 4,000 individuals aged 16-65 years living in Germany will be surveyed using online questionnaires. Each year, intentional indoor and outdoor tanning will be assessed. In addition, varying specific topics regarding skin cancer prevention, such as the utilization of skin cancer screening, will be addressed in the questionnaires. DISCUSSION: The findings of the NCAM-online will provide an important basis for the German Cancer Aid and Working Group on Dermatologic Prevention (Arbeitsgemeinschaft Dermatologische Prävention, ADP) to develop targeted prevention campaigns and projects aimed at preventing skin cancer. The explorative nature of the NCAM-online allows for the identification of new potential starting points for prevention and education. In addition, the longitudinal design allows for a description of the trend in the prevalence of intentional tanning. For tanning bed use, representative trend data from 2012 are available for Germany, to which NCAM-online will add annual data until 2027.

Cancer Incidence in a Population Living Near Radioactive Waste Storage of Uranium Mining in Stepnogorsk Area, Northern Kazakhstan.

OBJECTIVE: This study evaluates the impact of radioactive uranium waste storage facilities on cancer occurrence in nearby areas. METHODS: Current research evaluates the effect of radioactive uranium waste storage facilities on cancer epidemiology in nearby areas. The critical area had Aqsu, Kvartsitka, Zavodskoy and Stepnogorsk cities, which are located at a less than 5 km distance to the south of the Hydrometallurgical Plant tailings dump while the control group had Akkol region in 90 km from the source. The majority of population had lived in this territory more than the 30 years. Data were obtained from the Electronic Register of Cancer Patients of the Republic of Kazakhstan from 2001-2015, and 2,271 incident cases of cancer were registered. RESULTS: The most frequent malignancies were observed in the digestive organs (646 cases, 28%) and respiratory and intrathoracic organs (376 cases, 17%). The proportion of digestive organ cancers was higher in the critical group (560 cases out of 1913, 29%) than in the control group (86 cases out of 358, 24%). Additionally, respiratory organ cancers were more common in men, but the cancer incidence rate ratio was higher in the critical area. Notably, the study found that the cancer incidence rate ratios decreased over time, specifically for digestive, respiratory and female genital organs and breast cancer. CONCLUSION: In conclusion, while our study highlights significant differences in cancer incidence rates and frequencies between the critical and control groups, further analytical research, incorporating age-adjustment, is needed to provide a more conclusive evaluation of the potential impact of residence in proximity to the uranium mining waste storage on cancer occurrence in the study area.

Uranium in Drinking Water and Bladder Cancer: A Case-control Study in Michigan.

ABSTRACT: Uranium is naturally occurring in groundwater used for drinking; however, health risks from naturally occurring concentrations are uncertain. Uranium can cause both radiological and chemical toxicity following ingestion. Bladder and kidneys receive a dose when uranium is excreted into the urine. Investigate the association between uranium in drinking water and bladder cancer risk in a case-control study. A population-based bladder cancer case-control study was conducted in 11 counties of southeastern Michigan. A total of 411 cases and 566 controls provided drinking water and toenail samples and answered questions about lifestyle and residential history. Uranium was measured in drinking water and toenails, and its association with bladder cancer was assessed via unconditional logistic regression models. Median uranium concentration in water was 0.12 µg L -1 , with a maximum of 4.99 µg L -1 , and median uranium concentration in toenails was 0.0031 µg g -1 . In adjusted regression models, there was a suggestion of a protective effect among those exposed to the upper quartile of uranium in drinking water (HR = 0.64, 95% CI: 0.43, 0.96) and toenails (HR 0.66; 95% CI 0.45, 0.96) compared to those in the lowest quartile. Our objective is to investigate additional adjustment of drinking water source at home residence at time of recruitment to address potential selection bias and confounding attenuated results toward the null for drinking water uranium (HR = 0.68, 95% CI: 0.44, 1.05) and toenail uranium (HR = 0.80, 95% CI: 0.53, 1.20). This case-control study showed no increased risk of bladder cancer associated with uranium found in drinking water or toenails.

Dose Reconstruction for Epidemiological Studies among Ukrainian Chernobyl Cleanup Workers.

The present paper provides an overview of the methods and summarizes the results of estimating radiation doses and their uncertainties for Ukrainian-American epidemiological studies among the Chernobyl (Chornobyl) cleanup workers. After the Chernobyl accident occurred on April 26, 1986, more than 300,000 Ukrainian cleanup workers took part between 1986 and 1990 in decontamination and recovery activities at the site of the Chernobyl Nuclear Power Plant. The U.S. National Cancer Institute in collaboration with the Ukrainian National Research Center for Radiation Medicine conducted several epidemiological studies in this population. An important part of these studies was the reconstruction of the study participants' radiation doses and the assessment of uncertainties in doses. A method called realistic analytical dose reconstruction with uncertainty estimation (RADRUE) was used to calculate the doses from external irradiation during cleanup missions, which was the main exposure pathway for most study participants. At the initial phase of the accident during the atmospheric releases of radioactivity from the destroyed reactor, the cleanup workers also received doses from inhalation of radionuclides. In addition, study participants received doses at their places of residence, especially those who lived in highly contaminated areas. The radiation doses estimated for 2,048 male cleanup workers included in the Ukrainian-American epidemiological studies varied widely: (i) bone-marrow doses from external irradiation in the case-control study of leukemia of 1,000 cleanup workers ranged from 3.7 × 10-5 mGy to 3.3 Gy (mean = 92 mGy); (ii) thyroid doses in the case-control study of thyroid cancer in 607 persons from all exposure pathways combined were from 0.15 mGy to 9.0 Gy (mean = 199 mGy); (iii) gonadal doses in 183 cleanup workers from all exposure pathways combined in the study of germline mutations in the offspring after parental irradiation (trio study) ranged from 0.58 mGy to 4.1 Gy (mean = 392 mGy); (iv) thyroid doses in the human factor uncertainties study among 47 persons were from 20 mGy to 2.1 Gy (mean = 295 mGy); and (v) lung doses in the study of germline genetic variants associated with host susceptibility to COVID-19 estimated for 211 cleanup workers were from 0.024 mGy to 2.5 Gy (mean = 249 mGy). Doses of female cleanup workers were much lower than those of male cleanup workers: the mean doses for female cleanup workers were 27 mGy for 34 women included in the trio study and 56 mGy for 48 women participated in the study of germline genetic variants associated with host susceptibility to COVID-19. Uncertainties in dose estimates included two components: (i) inherent uncertainties arising from the stochastic random variability of the parameters used in exposure assessment and from a lack of knowledge about the true values of the parameters; and (ii) human factor uncertainties due to poor memory recall resulting in incomplete, inaccurate, or missing responses during personal interviews with cleanup workers conducted long after exposure. This paper also discusses possible developments and improvements in the methods to assess the radiation doses and associated uncertainties for cleanup workers.

[Translated article] Changes in the Location of Cutaneous Melanoma Over the Past 30 Years. A Retrospective Observational Study.

BACKGROUND: The location of cutaneous melanoma is associated with photoexposure. OBJECTIVES: To retrospectively analyze changes in the location of cutaneous melanoma over the past 30 years. PATIENTS AND METHODS: All patients treated at our hospital for cutaneous melanoma from 1988 through 2017 were prospectively collected. Data obtained in cases diagnosed from 1988 through June 2006 were compared to those diagnosed from July 2006 through 2017. RESULTS: A total of 1,937 patients (876 men and 1061 women; median age, 57 years; interquartile range 27) were diagnosed with primary cutaneous melanoma. The location of melanoma was head and neck (470 cases), trunk (745 cases), upper limbs (239 cases), and lower limbs (483 cases). From July 2006 through 2017 we detected an increase in the incidence of head and neck melanomas (19.9% vs 28.6%, p <0.001). A drop in the incidence of melanomas located in the lower extremities was also seen in women (39.8% vs 30.4%, p <0.001), and in the trunk men (57.5% vs 47.3%, p=0.003). In the multivariate analyses, only the decrease in melanomas located in lower extremities in women remained significant. CONCLUSION: The increased incidence of head and neck melanomas in both sexes and the decrease in trunk melanomas in men can be attributed to the aging of our population. The reduction in the incidence of melanomas in the lower extremities in women could be associated with changes in photoexposure patterns. Analyzing the factors possibly associated with these changes would contribute to better understanding the pathogenesis of cutaneous melanoma for prevention purposes.

Rapamycin Reduces Carcinogenesis and Enhances Survival in Mice when Administered after Nonlethal Total-Body Irradiation.

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment.

Mortality follow-up of Fernald Feed Materials Production Center workers exposed to uranium from 1951 to 1985.

OBJECTIVE: This follow-up study of uranium processing workers at the Fernald Feed Materials Production Center examines the relationship between radiation exposure and cancer and non-cancer mortality among 6403 workers employed for at least 30 days between 1951 and 1985. METHODS: We estimated cumulative, individual, annualised doses to 15 organs/tissues from external, internal and radon exposures. Vital status and cause of death were ascertained in 2017. The analysis employed standardised mortality ratios, Cox proportional hazards and Poisson regression models. Competing risk analysis was conducted for cardiovascular disease (CVD) mortality risk given several assumptions about risk independent of competing outcomes. Emphysema was examined to assess the potential for confounding by smoking. RESULTS: Vital status was confirmed for 98.1% of workers, with 65.1% deceased. All-cause mortality was less than expected in salaried but not hourly workers when compared with the US population. A statistically significant dose response was observed between external (but not total or internal) lung dose and lung cancer mortality (HR at 100 mGy adjusted for internal dose=1.45; 95% CI=1.05 to 2.01). Significantly increased HRs at 100 mGy dose to heart were observed for CVD (1.27; 95% CI=1.07 to 1.50) and ischaemic heart disease (1.30; 95% CI=1.07 to 1.58). CVD risk remained elevated regardless of competing risk assumptions. Both external and internal radiation were associated with emphysema. CONCLUSIONS: Lung cancer was associated with external dose, though positive dose responses for emphysema imply residual confounding by smoking. Novel use of competing risk analysis for CVD demonstrates leveraging retrospective data for future risk prediction.

Evaluation of PRAME immunohistochemistry in cutaneous vascular neoplasms reveals frequent expression in primary and post-irradiation cutaneous angiosarcomas.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) has been extensively studied in cutaneous melanocytic tumors and has proven valuable as a diagnostic adjunct in routine dermatopathology practice. However, its expression in cutaneous vascular neoplasms, particularly angiosarcomas (AS), remains largely unexplored. METHODS: To further explore PRAME expression in cutaneous AS, 18 cases of post-irradiation and 13 cases of primary cutaneous AS were evaluated for PRAME. For comparison, sections from 11 deep soft tissue/visceral AS, 10 Kaposi sarcomas, 8 microvenular hemangiomas, 7 infantile hemangiomas, 8 atypical vascular lesions, 6 epithelioid hemangioendotheliomas, 6 pyogenic granulomas, 6 papillary endothelial hyperplasias, 6 epithelioid hemangiomas, 3 capillovenous malformations, 3 hobnail hemangiomas, 2 spindle cell hemangiomas, 2 pseudomyogenic hemangioendotheliomas, and 2 composite hemangioendotheliomas were also retrieved. RESULTS: Overall, 22 of 31 (70.9%; 12 post-irradiation and 10 primary) cutaneous AS were positive for PRAME. In contrast, only 1 of 11 (9.1%) deep soft tissue/visceral AS showed diffuse and strong PRAME nuclear staining. All other tumor types were negative for PRAME, except for 5 of 7 (71.4%) infantile hemangiomas, which demonstrated rare (<5%; four cases) and 1+ (5-25%; one case) nuclear staining. CONCLUSIONS: In this study, we have demonstrated frequent nuclear PRAME expression in cutaneous AS. PRAME immunohistochemistry may serve as a valuable additional marker in selected clinical settings.

Poor Prognosis among Radiation-Associated Bladder Cancer Is Defined by Clinicogenomic Features.

Radiotherapy (RT) for prostate cancer has been associated with an increased risk for the development of bladder cancer. We aimed to integrate clinical and genomic data to better understand the development of RT-associated bladder cancer. A retrospective analysis was performed to identify control patients (CTRL; n = 41) and patients with RT-associated bladder cancer (n = 41). RT- and CTRL-specific features were then identified through integration and analysis of the genomic sequencing data and clinical variables. RT-associated bladder tumors were significantly enriched for alterations in KDM6A and ATM, whereas CTRL tumors were enriched for CDKN2A mutation. Globally, there were an increased number of variants within RT tumors, albeit at a lower variant allele frequency. Mutational signature analysis revealed three predominate motif patterns, with similarity to SBS2/13 (APOBEC3A), SBS5 (ERCC2/smoking), and SBS6/15 (MMR). Poor prognostic factors in the RT cohort include a short tumor latency, smoking status, the presence of the smoking and X-ray therapy mutational signatures, and CDKN2A copy number loss. Based on the clinical and genomic findings, we suggest at least two potential pathways leading to RT-associated bladder cancer: The first occurs in the setting of field cancerization related to smoking or preexisting genetic alterations and leads to the development of more aggressive bladder tumors, and the second involves RT initiating the oncogenic process in otherwise healthy urothelium, leading to a longer latency and less aggressive disease. SIGNIFICANCE: Clinicogenomic analysis of radiation-associated bladder cancer uncovered mutational signatures that, in addition to a short tumor latency, smoking, and CDKN2A loss, are associated with a poor outcome. These clinical and genomic features provide a potential method to identify patients with prostate cancer who are at an increased risk for the development of aggressive bladder cancer following prostate RT.

Practical guidance on the assessment of radiation risks for diagnostic radiological examinations.

Patient doses cannot be limited; instead, radiological examinations should be justified and optimised to ensure the necessary diagnostic or therapeutic effect with the lowest patient dose achievable. Assessment of the radiation risks from patient exposure is important part of the justification process. Hence, medical staff within the framework of their professional activities should possess necessary information on the data on radiation risk from different types of radiological procedures. An approach has been developed that allows considering age and gender dependences of the risk coefficients of radiogenic cancer and the age and gender distribution of patients for various radiological examinations to assess the individual radiation risk for patient and collective risk for population from medical exposure. The approach is based on a new expanded use of the effective dose concept proposed in ICRP Publication 147 and demonstrated using the medical exposure in the Russian Federation as the example. For 30 radiological examinations that compose about 80% of the collective dose from medical exposure of the public in the Russian Federation radiation risk was assessed based on calculated age and gender specific risk coefficients per unit effective dose. For the rest of the examinations a simplified approach was used to assess the risk, which was based on using an age and gender specific risk coefficient determined for one of 4 anatomical regions (head, neck, chest and abdomen) or for uniform irradiation of the whole body. The proposed approach allows significantly improving the assessment of the radiation risk while continuing to use the effective dose as a dosimetric quantity within the framework of the state program in the Russian Federation. As a result the collective risk from medical examinations in the Russian Federation in 2022 was lower by the factor of 3 compared to the previous assessment based on the effective dose with the nominal risk coefficient.

Treatment of secondary uterine malignancy following radiotherapy for cervical cancer: a study based on the SEER database.

BACKGROUND: Radiotherapy is one of the main treatments for cervical cancer. Long-term complications of radiation exposure include the emergence of secondary tumors. This is a retrospective study based on an American population. We discuss the optimal treatment modality for patients with radiation-induced secondary uterine malignancy based on the Surveillance, Epidemiology, and End Results database. METHODS: The study included patients with a definitive pathological diagnosis of cervical cancer who were diagnosed with a uterine malignant tumor ≥ 1 year later. Patients in whom cervical cancer was not the first tumor or patients with missing data were excluded. Univariate and multivariate analyses were performed using the COX regression model to screen independent prognostic factors affecting overall survival. Kaplan-Meier survival curves were analyzed using the R software package. RESULTS: We screened 142 patients with a secondary uterine malignancy after cervical cancer treatment, 115 patients with a secondary uterine malignancy after radiotherapy, and 27 patients with a secondary uterine malignancy who did not receive radiotherapy. The average latency period for developing a secondary tumor was 8 years, and 57.04% of the patients had a second tumor at ≥ 60 years of age. In patients with a secondary uterine malignancy after radiotherapy, surgery improved the prognosis [hazard ratio (HR), 0.374; 95% confidence interval (CI), 0.229-0.612], whereas radiotherapy and chemotherapy did not reduce the risk of death. In the subgroup analysis, the surgery plus chemotherapy group had a significantly better survival prognosis than the other groups (HR, 0.251; 95% CI, 0.122-0.515). CONCLUSIONS: The results suggest that the treatment modality in patients with secondary uterine malignancy after radiotherapy for cervical cancer has a significant impact on survival. The survival outcomes of patients receiving surgery combined with chemotherapy are superior to those of patients receiving other treatments.