Development of clinical application program for radiotherapy induced cancer risk calculation using Monte Carlo engine in volumetric-modulated arc therapy.

BACKGROUND: The purpose of this study is to develop a clinical application program that automatically calculates the effect for secondary cancer risk (SCR) of individual patient. The program was designed based on accurate dose calculations using patient computed tomography (CT) data and Monte Carlo engine. Automated patient-specific evaluation program was configured to calculate SCR. METHODS: The application program is designed to re-calculate the beam sequence of treatment plan using the Monte Carlo engine and patient CT data, so it is possible to accurately calculate and evaluate scatter and leakage radiation, difficult to calculate in TPS. The Monte Carlo dose calculation system was performed through stoichiometric calibration using patient CT data. The automatic SCR evaluation program in application program created with a MATLAB was set to analyze the results to calculate SCR. The SCR for organ of patient was calculated based on Biological Effects of Ionizing Radiation (BEIR) VII models. The program is designed to sequentially calculate organ equivalent dose (OED), excess absolute risk (EAR), excess relative risk (ERR), and the lifetime attributable risk (LAR) in consideration of 3D dose distribution analysis. In order to confirm the usefulness of the developed clinical application program, the result values from clinical application program were compared with the manual calculation method used in the previous study. RESULTS: The OED values calculated in program were calculated to be at most approximately 13.3% higher than results in TPS. The SCR result calculated by the developed clinical application program showed a maximum difference of 1.24% compared to the result of the conventional manual calculation method. And it was confirmed that EAR, ERR and LAR values can be easily calculated by changing the biological parameters. CONCLUSIONS: We have developed a patient-specific SCR evaluation program that can be used conveniently in the clinic. The program consists of a Monte Carlo dose calculation system for accurate calculation of scatter and leakage radiation and a patient-specific automatic SCR evaluation program using 3D dose distribution. The clinical application program that improved the disadvantages of the existing process can be used as an index for evaluating a patient treatment plan.

A Monte Carlo t Test to Evaluate Mesothelioma and Radiation in the US Transuranium and Uranium Registries.

A cluster of nine mesothelioma cases was observed among 341 registrants' deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.

RISK ASSESSMENT FOR RADON EXPOSURE IN VARIOUS INDOOR ENVIRONMENTS.

Using data from a number of radon surveys, it was assessed that on average, radon progeny concentrations in Canadian homes are about three times higher than in school buildings, 4.7 times higher than in public buildings and indoor workplaces, and 12 times higher than in outdoor air. Canadian statistics show that most Canadians spend ~70% of their time indoors at home, 20% indoors away from home and 10% in outdoors. Due to relatively higher radon concentration in residential homes and longer time spent indoors at home, the exposure at home contributes to 90% of the radon-induced lung-cancer risk.

Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment.

Strong evidence for the statistical association between radiation exposure and disease has been produced for thyroid cancer by epidemiological studies after the Chernobyl accident. However, limitations of the epidemiological approach in order to explore health risks especially at low doses of radiation appear obvious. Statistical fluctuations due to small case numbers dominate the uncertainty of risk estimates. Molecular radiation markers have been searched extensively to separate radiation-induced cancer cases from sporadic cases. The overexpression of the CLIP2 gene is the most promising of these markers. It was found in the majority of papillary thyroid cancers (PTCs) from young patients included in the Chernobyl tissue bank. Motivated by the CLIP2 findings we propose a mechanistic model which describes PTC development as a sequence of rate-limiting events in two distinct paths of CLIP2-associated and multistage carcinogenesis. It integrates molecular measurements of the dichotomous CLIP2 marker from 141 patients into the epidemiological risk analysis for about 13 000 subjects from the Ukrainian-American cohort which were exposed below age 19 years and were put under enhanced medical surveillance since 1998. For the first time, a radiation risk has been estimated solely from marker measurements. Cross checking with epidemiological estimates and model validation suggests that CLIP2 is a marker of high precision. CLIP2 leaves an imprint in the epidemiological incidence data which is typical for a driver gene. With the mechanistic model, we explore the impact of radiation on the molecular landscape of PTC. The model constitutes a unique interface between molecular biology and radiation epidemiology.

Thyroid Dose Estimates for a Cohort of Belarusian Children Exposed to (131)I from the Chernobyl Accident: Assessment of Uncertainties.

Deterministic thyroid radiation doses due to iodine-131 ((131)I) intake were reconstructed in a previous article for 11,732 participants of the Belarusian-American cohort study of thyroid cancer and other thyroid diseases in individuals exposed during childhood or adolescence to fallout from the Chernobyl accident. The current article describes an assessment of uncertainties in reconstructed thyroid doses that accounts for the shared and unshared errors. Using a Monte Carlo simulation procedure, 1,000 sets of cohort thyroid doses due to (131)I intake were calculated. The arithmetic mean of the stochastic thyroid doses for the entire cohort was 0.68 Gy. For two-thirds of the cohort the arithmetic mean of individual stochastic thyroid doses was less than 0.5 Gy. The geometric standard deviation of stochastic doses varied among cohort members from 1.33 to 5.12 with an arithmetic mean of 1.76 and a geometric mean of 1.73. The uncertainties in thyroid dose were driven by the unshared errors associated with the estimates of values of thyroid mass and of the (131)I activity in the thyroid of the subject; the contribution of shared errors to the overall uncertainty was small. These multiple sets of cohort thyroid doses will be used to evaluate the radiation risks of thyroid cancer and noncancer thyroid diseases, taking into account the structure of the errors in the dose estimates.

Impact of uncertainties in exposure assessment on estimates of thyroid cancer risk among Ukrainian children and adolescents exposed from the Chernobyl accident.

The 1986 accident at the Chernobyl nuclear power plant remains the most serious nuclear accident in history, and excess thyroid cancers, particularly among those exposed to releases of iodine-131 remain the best-documented sequelae. Failure to take dose-measurement error into account can lead to bias in assessments of dose-response slope. Although risks in the Ukrainian-US thyroid screening study have been previously evaluated, errors in dose assessments have not been addressed hitherto. Dose-response patterns were examined in a thyroid screening prevalence cohort of 13,127 persons aged <18 at the time of the accident who were resident in the most radioactively contaminated regions of Ukraine. We extended earlier analyses in this cohort by adjusting for dose error in the recently developed TD-10 dosimetry. Three methods of statistical correction, via two types of regression calibration, and Monte Carlo maximum-likelihood, were applied to the doses that can be derived from the ratio of thyroid activity to thyroid mass. The two components that make up this ratio have different types of error, Berkson error for thyroid mass and classical error for thyroid activity. The first regression-calibration method yielded estimates of excess odds ratio of 5.78 Gy(-1) (95% CI 1.92, 27.04), about 7% higher than estimates unadjusted for dose error. The second regression-calibration method gave an excess odds ratio of 4.78 Gy(-1) (95% CI 1.64, 19.69), about 11% lower than unadjusted analysis. The Monte Carlo maximum-likelihood method produced an excess odds ratio of 4.93 Gy(-1) (95% CI 1.67, 19.90), about 8% lower than unadjusted analysis. There are borderline-significant (p = 0.101-0.112) indications of downward curvature in the dose response, allowing for which nearly doubled the low-dose linear coefficient. In conclusion, dose-error adjustment has comparatively modest effects on regression parameters, a consequence of the relatively small errors, of a mixture of Berkson and classical form, associated with thyroid dose assessment.

Non-targeted effects of ionizing radiation: implications for risk assessment and the radiation dose response profile.

Radiation risks at low doses remain a hotly debated topic. Recent experimental advances in our understanding of effects occurring in the progeny of irradiated cells, and/or the non-irradiated neighbors of irradiated cells (i.e., non-targeted effects associated with exposure to ionizing radiation), have influenced this debate. The goal of this document is to summarize the current status of this debate and speculate on the potential impact of non-targeted effects on radiation risk assessment and the radiation dose response profile.

A quantitative assessment of the burden and distribution of Lisch nodules in adults with neurofibromatosis type 1.

PURPOSE: The presence of two or more Lisch nodules (melanocytic hamartomas of the iris) is one of seven diagnostic criteria for neurofibromatosis type 1 (NF1), a common monogenic disorder of dysregulated neurocutaneous growth. The hypothesis that Lisch nodules arise secondary to exposure to ultraviolet (UV) radiation from sunlight was investigated. METHODS: Lisch nodule burden was mapped and quantified in the irides of 77 adults with NF1. Lifetime sunlight (UV radiation) exposure was inventoried, NF1 neurocutaneous severity determined, and two NF1 mutations predictive of severity selectively genotyped. RESULTS: There was high interindividual variability in Lisch nodule burden. Lisch nodules were primarily located in the inferior hemifield (half) of the iris, regardless of its color (P = 3.0 x 10(-20)). Light irides harbored significantly more Lisch nodules than dark irides (P = 4.8 x 10(-5)). There was no statistically significant correlation of Lisch nodule burden to lifetime sunlight exposure "dose" or NF1 neurocutaneous severity. CONCLUSIONS: The difference in Lisch nodule burden between the superior and inferior iris hemifields is most likely due to the sunlight-shielding effects on the superior half by periocular structures. The difference in Lisch nodule burden between light and dark irides is probably due to the photoprotective effects of pigmentation. The genes underlying the control of iris color may thus be viewed as modifiers of severity of Lisch nodule burden in NF1. Given the role of UV radiation and, presumably, DNA damage in Lisch nodule pathogenesis, "benign tumor of the iris," not "hamartoma," may be a better descriptor.

The risk of developing a second cancer after receiving craniospinal proton irradiation.

The purpose of this work was to compare the risk of developing a second cancer after craniospinal irradiation using photon versus proton radiotherapy by means of simulation studies designed to account for the effects of neutron exposures. Craniospinal irradiation of a male phantom was calculated for passively-scattered and scanned-beam proton treatment units. Organ doses were estimated from treatment plans; for the proton treatments, the amount of stray radiation was calculated separately using the Monte Carlo method. The organ doses were converted to risk of cancer incidence using a standard formalism developed for radiation protection purposes. The total lifetime risk of second cancer due exclusively to stray radiation was 1.5% for the passively scattered treatment versus 0.8% for the scanned proton beam treatment. Taking into account the therapeutic and stray radiation fields, the risk of second cancer from intensity-modulated radiation therapy and conventional radiotherapy photon treatments were 7 and 12 times higher than the risk associated with scanned-beam proton therapy, respectively, and 6 and 11 times higher than with passively scattered proton therapy, respectively. Simulations revealed that both passively scattered and scanned-beam proton therapies confer significantly lower risks of second cancers than 6 MV conventional and intensity-modulated photon therapies.

Estimating the risk of cancer associated with imaging related radiation during surveillance for stage I testicular cancer using computerized tomography.

PURPOSE: Computerized tomography has a critical role in the surveillance of stage I nonseminomatous germ cell tumors of the testis. Some protocols call for up to 16 computerized tomography scans over 5 years, thereby exposing young patients to a significant amount of radiation. We estimated the lifetime risk of cancer incidence and cancer death from imaging related radiation received during surveillance of stage I nonseminomatous germ cell tumor. MATERIALS AND METHODS: Using a model with a 64-slice computerized tomography scanner obtaining images of the abdomen and pelvis with or without chest in a standardized, phantom male patient, organ specific radiation doses were estimated using Monte Carlo simulation techniques. Lifetime attributable risks of cancer were estimated using the approach outlined in the Biological Effects of Ionizing Radiation VII Phase 2 report. RESULTS: With a 5-year surveillance protocol as suggested by the National Comprehensive Cancer Network, lifetime cancer risk ranged from 1 in 52 (1.9%) for an 18-year-old to 1 in 63 for a 40-year-old patient (1.2%). If chest computerized tomography is also performed the risk increases to 1 in 39 (2.6%) and 1 in 85 (1.6%), respectively. Lung and colon cancer accounted for most of the risk. The relative risk of a secondary malignancy with surveillance compared to a single scan after retroperitoneal lymph node dissection is approximately 15.2. CONCLUSIONS: Computerized tomography used in testicular cancer surveillance protocols imparts large radiation doses and is associated with a significant risk of cancer. This risk should be factored into counseling patients with stage I nonseminomatous germ cell tumor.

Promotion of initiated cells by radiation-induced cell inactivation.

Cells on the way to carcinogenesis can have a growth advantage relative to normal cells. It has been hypothesized that a radiation-induced growth advantage of these initiated cells might be induced by an increased cell replacement probability of initiated cells after inactivation of neighboring cells by radiation. Here Monte Carlo simulations extend this hypothesis for larger clones: The effective clonal expansion rate decreases with clone size. This effect is stronger for the two-dimensional than for the three-dimensional situation. The clones are irregular, far from a circular shape. An exposure-rate dependence of the effective clonal expansion rate could come in part from a minimal recovery time of the initiated cells for symmetric cell division.

Reliability and validity of a bioimpedance measurement device in the assessment of UVR damage to the skin.

Ultraviolet radiation (UVR) is the primary cause of skin cancers. However, it is difficult to evaluate the amount of UVR absorbed into the skin retrospectively. Therefore, objective and non-invasive quantitative method would be valuable for epidemiological UVR exposure assessment. Photodamage reduces the amount of bound water in the skin, and thus, measuring the skin's dielectric constant can provide an opportunity for assessing the cumulative UVR exposure. The purpose of the study was to assess the reliability and validity of the bioimpedance device, Moisture Meter-D. The measurements were performed on 100 subjects at three separate measurement times. A questionnaire was used to obtain information on the host factors and on the past UVR exposure. The biological samples, to determine the elastin proportion of the dermis, were collected. Some long-term as well as seasonal variations in the dielectric constants were detected. Also, a weak relationship between the dielectric constant and the UVR exposure indicators and host factors was observed. The MoistureMeter-D appears not to measure structural alterations in the skin caused by photodamage, and thus it is not a valid instrument for the assessment of photodamage, i.e., past UVR exposure.

Therapeutic efficacy as predicted by quantitative assessment of murine RIF-1 tumour pH and phosphorous metabolite response during hyperthermia: an in vivo 31P NMR study.

Described herein are the initial findings from an 'in-magnet' 31P NMR compatible hyperthermia system capable of concurrently heating and monitoring the metabolic response of murine tumours; the murine radiation induced fibrosarcoma (RIF-1) was employed for these studies. At thermal doses sufficient to raise tumour temperature to 41.5 and 43 degrees C for a period of 30 min, a marked and rapid decrease in nucleoside triphosphate concentration and in pH was observed during the heating period, while inorganic phosphate concentration increased significantly but more gradually. These 31P NMR determined metabolic indices remained depressed/elevated throughout a 1.5 h post-hyperthermia monitoring period. Importantly, these metabolic indices correlated significantly with specific growth delay. This suggests a possible role for NMR spectroscopy in early assessment, and perhaps control, of therapeutic response to hyperthermia.

Single-track effects and new directions in GCR risk assessment.

Light flashes in the eye as recorded by astronauts on missions outside the geomagnetosphere are presumably caused by single particle traversals of galactic cosmic rays traversing the retina. Although these flashes are not considered to have deleterious short- or long-term effects on vision, they are testimony that the body can detect single particle traversals. The frequencies of the flashes implicate ions in the charge range of 6 to 8 (i.e., carbon and/or oxygen ions). Other particles with higher charge and causing more ionization are present at lower frequencies. The possibility of the importance of such single-track effects in radiation carcinogenesis and other late effects suggest that a risk assessment system based on particle fluence rather than absorbed dose might be useful for assessing risk on long-term space missions. Such a system based on the concept of a risk cross section is described. Human cancer risk cross sections obtained from recently compiled A-bomb survival data are presented, and problems involving the determination of the LET-dependence of such cross sections are discussed.

Assessment of clinicopathologic features of colorectal mucinous adenocarcinoma.

The purpose of this report is to analyze the clinicopathologic features of colorectal mucinous adenocarcinoma (MC), which is generally believed to have a poor prognosis, in an attempt to assess ways in which the surgical outcome can be improved. Clinicopathologic features of 44 patients with MC (6.6%), from among 662 patients with primary colorectal cancers, were compared with those of 545 patients with nonmucinous (non-MC) adenocarcinoma. MC is more likely to invade the adjacent viscera (29% versus 10%, p < 0.005) and show more extensive lymph node involvement beyond the pericolonic region (50% versus 26%, p < 0.005) than non-MC. Based on these findings, a more aggressive attitude toward surgical intervention is recommended, including extensive lymph node dissection and the resection of adjacent organs that seems to be affected macroscopically, to improve the surgical outcome of this clinical entity.

Incidence and management of secondary malignancies in patients with retinoblastoma and Ewing's sarcoma.

Childhood cancer survivors at highest risk of developing a secondary malignancy are those with hereditary retinoblastoma. The majority of such secondary cancers will be sarcomas, most commonly of bone. One-third of these occur outside a typical radiation field, commonly in an extremity. Bone sarcoma is also the most commonly reported secondary cancer to develop among survivors of Ewing's sarcoma. In this group, radiation doses greater than 60 Gy as well as alkylating agent chemotherapy have been identified as contributors to the increased risk. The prognosis for patients with a secondary sarcoma has been poor, with few cures reported to date. However, an aggressive, combined modality approach, including radical resection, postoperative radiation, and adjuvant chemotherapy, may improve the survival rate.

Galactic cosmic rays and cell-hit frequencies outside the magnetosphere.

An evaluation of the exposure of space travelers to galactic cosmic radiation outside the earth's magnetosphere is made by calculating fluences of high-energy primary and secondary particles with various charges traversing a sphere of area 100 microns2. Calculations relating to two shielding configurations are presented: the center of a spherical aluminum shell of thickness 1 g/cm2, and the center of a 4 g/cm2 thick aluminum spherical shell within which there is a 30 g/cm2 diameter spherical water phantom with the point of interest 5 g/cm2 from the surface. The area of 100 microns2 was chosen to simulate the nucleus of a cell in the body. The frequencies as a function of charge component in both shielding configurations reflects the odd-even disparity of the incident particle abundances. For a three-year mission, 33% of the cells in the more heavily shielded configuration would be hit by at least one particle with Z greater than 10. Six percent would be hit by at least two such particles. This emphasizes the importance of studying single high-Z particle effects both on cells which might be "at risk" for cancer induction and on critical neural cells or networks which might be vulnerable to inactivation by heavy charged particle tracks. Synergistic effects with the more numerous high-energy protons and helium ions cannot be ruled out. In terms of more conventional radiation risk assessment, the dose equivalent decreased by a factor of 2.85 from free space to that in the more heavily shielded configuration. Roughly half of this was due to the decrease in energy deposition (absorbed dose) and half to the decrease in biological effectiveness (quality factor).

Operative strategy for thyroid cancer. Is total thyroidectomy worth the price?

The authors conducted a retrospective analysis with 5- to 30-year follow-up on 109 patients in order to determine the optimum management of nonmedullary thyroid cancer. Results of total thyroidectomy were compared to partial thyroidectomy, among patients well matched for prognostic indicators. No differences in cancer mortality or recurrence rates were evident. However, there were significantly more complications when total thyroidectomy was employed. In view of these results, partial thyroidectomy is recommended as the treatment of choice for nonmedullary thyroid cancer.