Are radiation-induced cavernomas clinically relevant findings? Results from long-term follow-up with brain magnetic resonance imaging of childhood cancer survivors.

INTRODUCTION: Radiation-induced cavernomas (RIC) after cranial radiotherapy have an unknown risk of hemorrhage. Zabramski magnetic resonance imaging (MRI) classification is touted as being able to indicate non-radiation-induced cavernomas hemorrhage risk. The aim of our study was to assess the hemorrhage risk of RIC during long-term follow-up of childhood cancer survivors based on brain MRI examinations. PATIENTS AND METHODS: We analyzed retrospectively long-term follow-up data of 36 childhood cancer survivors after initial diagnosis with acute leukemia (n = 18) or brain tumor (n = 18), all treated with cranial radiotherapy. Detected RIC in long-term follow-up brain MRI (1.5 or 3 Tesla) were classified following the Zabramski MRI classification and were categorized into "high" (Zabramski type I, II or V) or "low" (type III or IV) risk of hemorrhage. RESULTS: 18 patients (50%) showed RIC with a significant relation to the original tumor entity (p = 0.023) and the cumulative radiation dose to the brain (p = 0.016): all 9 childhood cancer survivors diagnosed with medulloblastoma developed RIC. We classified RIC in only 3/36 childhood cancer survivors (8%) (1 patient with acute lymphoblastic leukemia [Zabramski type II] and 2 patients with medulloblastoma [type I and type II]) as high risk for hemorrhage, the remaining RIC were classified as Zabramski type IV with low risk for hemorrhage. None of the childhood cancer survivors with RIC showed symptomatic hemorrhages. CONCLUSIONS: RIC are common late effects in childhood cancer survivors treated with cranial radiotherapy affecting half of these patients. However, only a few RIC (occurring in 8% of all reviewed childhood cancer survivors) were classified as high risk for hemorrhage and none of the childhood cancer survivors with RIC developed symptomatic hemorrhages. Thus, we conclude that RIC are low-risk findings in brain MRI and the course is mainly benign.

UV Signature Mutations Reclassify Salivary High-grade Neuroendocrine Carcinomas as Occult Metastatic Cutaneous Merkel Cell Carcinomas.

Salivary high-grade neuroendocrine carcinomas (NECs) are rare, occur predominantly in the parotid gland, and are difficult to differentiate from metastatic cutaneous Merkel cell carcinomas (MCCs), which have overlapping morphologic, immunophenotypic, and molecular profiles. Oncogenic Merkel cell polyomavirus (MCPyV), found in 70% to 80% of MCCs, has also been reported in a few salivary NECs, but this is controversial. A promising biomarker to distinguish the 2 tumor types are UV signature mutations. UV signature mutations indicate a sun damage-induced mechanism of pathogenesis and recently have been found to be highly prevalent in MCPyV-negative MCCs but would be inconsistent with salivary origin. Here, we examine UV signature mutations as a molecular marker to distinguish primary salivary high-grade NEC from MCC. Whole exome DNA sequencing was performed on matched tumor-normal tissue from 4 MCPyV-negative high-grade salivary NECs with no other primary source identified, as well as 3 melanomas and 3 lung NECs as positive and negative controls, respectively. UV signature mutations were found in all salivary NECs, when defined as ≥60% of total mutations being C-to-T transitions at dipyrimidine sites, and when compared with known human cancer-related mutational signatures. The presence of UV signature mutations in salivary high-grade NECs strongly favors these to be occult metastatic MCCs. True salivary primary NECs are likely exceedingly rare. When a high-grade NEC is encountered in the salivary gland, the presence of UV signature mutations or MCPyV may be useful to exclude occult unknown primary MCC.

Histological intralesional heterogeneity of actinic keratoses relates to field cancerization.

BACKGROUND/OBJECTIVES: Histological heterogeneity within distinct actinic keratosis (AK) lesions has been described and might serve as an additional feature of AKs. We aimed to investigate and quantify the histological heterogeneity of AKs regarding different grading systems. METHODS AND MATERIAL: We assessed the histology of 3 mm biopsies of AK lesions located on the scalp or face. We documented basal proliferation (PRO I-III), histological grade (AK I-III) and determined the overall classification of each lesion. RESULTS: Of the 305 lesions included, 48 (15.7 %) lesions were classified as AK I, 152 (49.8 %) as AK II and 105 (34.4 %) as AK III. 33 AKs (10.8 %) showed no basal proliferation, 94 (30.8 %) were graded as PRO I, 99 (32.5 %) as PRO II and 79 (25.9 %) as PRO III. One histological grade and basal growth pattern per lesion was observed in 94 (30.8 %) and 104 (34.1 %) cases respectively, two grades in 170 (55.7 %) and 168 (55.1 %) cases, and three grades in 41 (13.4 %) and 33 (10.8 %) cases (Chi-squared test, p < 0.0001). CONCLUSIONS: By analogy with the clinical heterogeneity of field cancerization, AKs show a high histological grade heterogeneity even within small lesions. Variations in AK grading reflect the heterogeneity of the cancerization field and might serve as additional feature.

Cancer mortality and incidence following external occupational radiation exposure: an update of the 3rd analysis of the UK national registry for radiation workers.

BACKGROUND: This study provides direct evidence of cancer risk from low dose and dose rate occupational external radiation exposures. METHODS: Cancer mortality and incidence were studied in relation to external radiation exposure in the National Registry for Radiation Workers. A cohort of 167,003 workers followed for an average of 32 years was analysed using Poisson regression methods. RESULTS: Mortality and incidence risks were significantly raised for the group of all malignant neoplasms excluding leukaemia (ERR/Sv mortality = 0.28; 90%CI: 0.06, 0.53, ERR/Sv incidence = 0.28; 90%CI: 0.10, 0.48) but with narrower confidence bounds compared with the previous analysis of this cohort reflecting the increased statistical power from the additional 10 years of follow-up information. The linear trends in relative risk for both mortality and incidence of these cancers remained statistically significantly raised when information relating to cumulative doses above 100 mSv was excluded (ERR/Sv mortality = 1.42; 90%CI: 0.51, 2.38 and ERR/Sv incidence = 1.18; 90%CI: 0.47, 1.92). CONCLUSIONS: This study improved the precision of the cancer risk estimates seen in the third analysis of the NRRW cohort. The overall results remain consistent with the risk estimates from the Life Span Study and those adopted in the current ICRP recommendations.

[Hiroshima/Nagasaki survivors and their offspring: results of longterm epidemiological studies]. / Les survivants d'Hiroshima/Nagasaki et leur descendance - Les enseignements d'une étude épidémiologique à long terme.

After the atomic bombing of Hiroshima and Nagasaki, long-term epidemiological studies were undertaken on the irradiated survivors and their offspring, and are still underway. These thorough studies involving tens of thousands of persons and published in hundreds of papers have shown a moderate increase in cancer incidence for irradiated survivors, with limited impact on their life span (loss of one year at most). In studies on the offspring of these survivors, no statistically significant deleterious effect on malformation frequency, incidence of mutations or mortality from cancer and other diseases has been seen so far. These data are actually the basis for current radiation safety levels; they show that health risks from radiation are limited, but they are not applicable to complex situations such as nuclear power station accidents that involve diverse types of radiation as well as contamination by radioactive materials.

Cancer risks in a population-based study of 70,570 agricultural workers: results from the Canadian census health and Environment cohort (CanCHEC).

BACKGROUND: Agricultural workers may be exposed to potential carcinogens including pesticides, sensitizing agents and solar radiation. Previous studies indicate increased risks of hematopoietic cancers and decreased risks at other sites, possibly due to differences in lifestyle or risk behaviours. We present findings from CanCHEC (Canadian Census Health and Environment Cohort), the largest national population-based cohort of agricultural workers. METHODS: Statistics Canada created the cohort using deterministic and probabilistic linkage of the 1991 Canadian Long Form Census to National Cancer Registry records for 1992-2010. Self-reported occupations were coded using the Standard Occupational Classification (1991) system. Analyses were restricted to employed persons aged 25-74 years at baseline (N = 2,051,315), with follow-up until December 31, 2010. Hazard ratios (HR) and 95% confidence intervals (CI) were modeled using Cox proportional hazards for all workers in agricultural occupations (n = 70,570; 70.8% male), stratified by sex, and adjusted for age at cohort entry, province of residence, and highest level of education. RESULTS: A total of 9515 incident cancer cases (7295 in males) occurred in agricultural workers. Among men, increased risks were observed for non-Hodgkin lymphoma (HR = 1.10, 95% CI = 1.00-1.21), prostate (HR = 1.11, 95% CI = 1.06-1.16), melanoma (HR = 1.15, 95% CI = 1.02-1.31), and lip cancer (HR = 2.14, 95% CI = 1.70-2.70). Decreased risks in males were observed for lung, larynx, and liver cancers. Among female agricultural workers there was an increased risk of pancreatic cancer (HR = 1.36, 95% CI = 1.07-1.72). Increased risks of melanoma (HR = 1.79, 95% CI = 1.17-2.73), leukemia (HR = 2.01, 95% CI = 1.24-3.25) and multiple myeloma (HR = 2.25, 95% CI = 1.16-4.37) were observed in a subset of female crop farmers. CONCLUSIONS: Exposure to pesticides may have contributed to increased risks of hematopoietic cancers, while increased risks of lip cancer and melanoma may be attributed to sun exposure. The array of decreased risks suggests reduced smoking and alcohol consumption in this occupational group compared to the general population.

[The Problem of the Relationship of the Chromosome Aberration Frequency in Peripheral Blood Lymphocytes with the Risk of Disease Development Including after Irradiation].

This paper presents an analysis of the data published in the scientific literature in connection with the prob- lem of forecasting the risk of development of malignant and non-malignant diseases by chromosome aberra- tion frequencies in cultures of human peripheral- blood lymphocytes. This question is closely linked with the concept of a common chromosomal instability. At the end of the twentieth century evidence of the possibility of such forecast for malignant diseases appeared when cytogenetic indices did not exceed control values on the whole. At the same time there are significant uncertainties due to interindividual and intraindividual variability. In addition, there are significant difficulties concerning distinction of chromosome aberrations induced by environmental influences (for example, radiation) and those due to the possibility of internal processes in the body. For non-malignant diseases the applicability of a similar approach to risk evaluation is not sufficiently substantiated.

[UV-irradiation-induced skin cancer as a new occupational disease]. / UV-Licht-induzierter Hautkrebs als neue Berufskrankheit.

With the revision of the German Ordinance on Occupational Diseases, skin cancer due to UV irradiation was amended as a new occupational disease to the list of occupational diseases in Germany. The new occupational disease BK 5103 has the following wording: "Squamous cell carcinoma or multiple actinic keratosis of the skin caused by natural UV irradiation". Actinic keratoses are to be considered as multiple according to this new occupational diseases if they occur as single lesions of more than five annually, or are confluent in an area > 4 cm(2) (field cancerization). It is estimated that more than 2.5 million employees are exposed to natural UV irradiation due to their work (outdoor workers) in Germany and therefore have an increased risk of skin cancer. In this article the medical and technical prerequisites which have to be fulfilled for this new occupational disease in Germany are introduced.

[SYNERGISM OF PRECONCEPTIVE RADIATION EXPOSURE AND PARENTS' ONCO-PATHOLOGY IN THE RISE OF CARCINOGENIC RISK IN THE OFFSPRINGS OF PROFESSIONAL EMPLOYEES].

The problem of carcinogenic risk in offsprings of individuals exposed to radiation is challenging and insufficiently studied. In that there are no evaluations of the interaction between radiation and non-radiation factors. The aim of the study was the analysis of interaction of preconceptive radiation exposure and parents' onco-pathology in cancer mortality in offsprings (F1) of workers (fathers) of the Mayak Production Association exposed to a wide range of doses of radiation over a year prior conception. The number of offspring is 8191 individuals (4180 men and 4011 women). The analysis was performed with the use of fourfold table and eightfold tables. The interaction offactors was estimated on the base of the additive and multiplicative models. The studied factors were independent. The odds ratio (OR) of cancer mortality in the offspring with parents' oncopathology (1.43) was insignificant. OR of cancer mortality in preconceptive radiation exposure in a dose over 110 mGy and without parents' onco-pathology was 2.61 (1.52-4.49), and in their combination--3.86 (1.93-7.71). Index of synergism of preconceptive radiation exposure and parents' onco-patholog in the rise of carcinogenic risk in the offspring was 1.34 and the character of their interaction was multiplicative. Thus, for the first time there was established the interaction between radiation and non-radiation factors in the synergism sort in the increase of carcinogenic risk in the offspring of people exposed to radiation.

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma (MCC, cutaneous neuroendocrine carcinoma) is a rare form of tumor of unclear histogenesis which predominantly occurs in elderly patients on areas exposed to the sun. A higher incidence and occurrence in younger people is predominantly found in immunosuppressed persons which is why a pathogenetic role is also attributed to immunosuppression in addition to ultraviolet (UV) radiation. Additionally, in 80% of cases clonally integrated polyomavirus (Merkel cell polyomavirus, MCPyV) could be detected. Clinically MCC represents an uncharacteristic tumor. Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g. chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, TdT and PAX-5 are immunohistochemically positive. In most cases CM2B4, an antibody against MCPyV is also positive. Expression of p63 has been observed in some of the cases and in some studies was associated with a favorable prognosis. The markers thyroid transcription factor 1, mammalian achaete scute complex like 1, vimentin, S-100 and CK7 are not normally expressed by MCC. The prognosis is primarily dependent on tumor size and the lymph node status. The presence of intralymphatic tumor complexes is associated with a higher rate of local recurrence and lymph node metastasis. A larger number of intratumoral cytotoxic T-lymphocytes is accompanied by a favorable prognosis and the presence of > 50% of K-67+ neoplastic cells with an unfavorable prognosis. Further morphological, phenotypical and genetic factors have not yet been validated in larger cohorts with respect to the prognostic relevance.

Cancer mortality among women frequently exposed to radiographic examinations for spinal disorders.

We studied cancer mortality in a cohort of 5,573 women with scoliosis and other spine disorders who were diagnosed between 1912 and 1965 and were exposed to frequent diagnostic X-ray procedures. Patients were identified from medical records in 14 orthopedic medical centers in the United States and followed for vital status and address through December 31, 2004, using publicly available regional, state and nationwide databases. Causes of death were obtained from death certificates or through linkage with the National Death Index (NDI). Statistical analyses included standardized mortality ratios (SMR = observed/expected) based on death rates for U.S. females and internal comparisons using Cox regression models with attained age as the time scale. Diagnostic radiation exposure was estimated from radiology files for over 137,000 procedures; estimated average cumulative radiation doses to the breast, lung, thyroid and bone marrow were 10.9, 4.1, 7.4 and 1.0 cGy, respectively. After a median follow-up period of 47 years, 1527 women died, including 355 from cancer. Cancer mortality was 8% higher than expected (95% CI = 0.97-1.20). Mortality from breast cancer was significantly elevated (SMR = 1.68; 95% CI: 1.38-2.02), whereas death rates from several other cancers were below expectation, in particular lung (SMR = 0.77), cervical (SMR = 0.31), and liver (SMR = 0.17). The excess relative risk (ERR) for breast cancer mortality increased significantly with 10-year lagged radiation dose to the breast (ERR/Gy = 3.9; 95% CI: 1.0-9.3).

Radiation doses and cancer risks in the Marshall Islands associated with exposure to radioactive fallout from Bikini and Enewetak nuclear weapons tests: summary.

Nuclear weapons testing conducted at Bikini and Enewetak Atolls during 1946-1958 resulted in exposures of the resident population of the present-day Republic of the Marshall Islands to radioactive fallout. This paper summarizes the results of a thorough and systematic reconstruction of radiation doses to that population, by year, age at exposure, and atoll of residence, and the related cancer risks. Detailed methods and results are presented in a series of companion papers in this volume. From our analysis, we concluded that 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in measurable fallout deposition on one or more of the inhabited atolls of the Marshall Islands. In this work, we estimated deposition densities (kBq m(-2)) of all important dose-contributing radionuclides at each of the 32 atolls and separate reef islands of the Marshall Islands. Quantitative deposition estimates were made for 63 radionuclides from each test at each atoll. Those estimates along with reported measurements of exposure rates at various times after fallout were used to estimate radiation absorbed doses to the red bone marrow, thyroid gland, stomach wall, and colon wall of atoll residents from both external and internal exposure. Annual doses were estimated for six age groups ranging from newborns to adults. We found that the total deposition of 137Cs, external dose, internal organ doses, and cancer risks followed the same geographic pattern with the large population of the southern atolls receiving the lowest doses. Permanent residents of the southern atolls who were of adult age at the beginning of the testing period received external doses ranging from 5 to 12 mGy on average; the external doses to adults at the mid-latitude atolls ranged from 22 to 59 mGy on average, while the residents of the northern atolls received external doses in the hundreds to over 1,000 mGy. Internal doses varied significantly by age at exposure, location, and organ. Except for internal doses to the thyroid gland, external exposure was generally the major contributor to organ doses, particularly for red bone marrow and stomach wall. Internal doses to the stomach wall and red bone marrow were similar in magnitude, about 1 mGy to 7 mGy for permanent residents of the southern and mid-latitude atolls. However, adult residents of Utrik and Rongelap Island, which are part of the northern atolls, received much higher internal doses because of intakes of short-lived radionuclides leading to doses from 20 mGy to more than 500 mGy to red bone marrow and stomach wall. In general, internal doses to the colon wall were four to ten times greater than those to the red bone marrow and internal doses to the thyroid gland were 20 to 30 times greater than to the red bone marrow. Adult internal thyroid doses for the Utrik community and for the Rongelap Island community were about 760 mGy and 7,600 mGy, respectively. The highest doses were to the thyroid glands of young children exposed on Rongelap at the time of the Castle Bravo test of 1 March 1954 and were about three times higher than for adults. Internal doses from chronic intakes, related to residual activities of long-lived radionuclides in the environment, were, in general, low in comparison with acute exposure resulting from the intakes of radionuclides immediately or soon after the deposition of fallout. The annual doses and the population sizes at each atoll in each year were used to develop estimates of cancer risks for the permanent residents of all atolls that were inhabited during the testing period as well as for the Marshallese population groups that were relocated prior to the testing or after it had begun. About 170 excess cancers (radiation-related cases) are projected to occur among more than 25,000 Marshallese, half of whom were born before 1948. All but about 65 of those cancers are estimated to have already been expressed. The 170 excess cancers are in comparison to about 10,600 cancers that would spontaneously arise, unrelated to radioactive fallout, among the same cohort of Marshallese people.

Acute and chronic intakes of fallout radionuclides by Marshallese from nuclear weapons testing at Bikini and Enewetak and related internal radiation doses.

Annual internal radiation doses resulting from both acute and chronic intakes of all important dose-contributing radionuclides occurring in fallout from nuclear weapons testing at Bikini and Enewetak from 1946 through 1958 have been estimated for the residents living on all atolls and separate reef islands of the Marshall Islands. Internal radiation absorbed doses to the tissues most at risk to cancer induction (red bone marrow, thyroid, stomach, and colon) have been estimated for representative persons of all population communities for all birth years from 1929 through 1968, and for all years of exposure from 1948 through 1970. The acute intake estimates rely on a model using, as its basis, historical urine bioassay data, for members of the Rongelap Island and Ailinginae communities as well as for Rongerik residents. The model also utilizes fallout times of arrival and radionuclide deposition densities estimated for all tests and all atolls. Acute intakes of 63 radionuclides were estimated for the populations of the 20 inhabited atolls and for the communities that were relocated during the testing years for reasons of safety and decontamination. The model used for chronic intake estimates is based on reported whole-body, urine, and blood counting data for residents of Utrik and Rongelap. Dose conversion coefficients relating intake to organ absorbed dose were developed using internationally accepted models but specifically tailored for intakes of particulate fallout by consideration of literature-based evidence to choose the most appropriate alimentary tract absorption fraction (f1) values. Dose estimates were much higher for the thyroid gland than for red marrow, stomach wall, or colon. The highest thyroid doses to adults were about 7,600 mGy for the people exposed on Rongelap; thyroid doses to adults were much lower, by a factor of 100 or more, for the people exposed on the populated atolls of Kwajalein and Majuro. The estimates of radionuclide intake and internal radiation dose to the Marshallese that are presented in this paper are the most complete available anywhere and were used to make projections of lifetime cancer risks to the exposed populations, which are presented in a companion paper in this volume.

Projected lifetime cancer risks from exposure to regional radioactive fallout in the Marshall Islands.

Radioactive fallout from nuclear test detonations during 1946-1958 at Bikini and Enewetak Atolls in the Marshall Islands (MI) exposed populations living elsewhere in the MI archipelago. A comprehensive analysis, presented in seven companion papers, has produced estimates of tissue-specific radiation absorbed dose to MI residents at all historically inhabited atolls from internal (ingested) and external irradiation resulting from exposure to radioactive fallout, by calendar year, and by age of the population at time of exposure. The present report deals, for the first time, with the implications of these doses for cancer risk among exposed members of the MI population. Radiation doses differed by geographic location and year of birth, and radiation-related cancer risk depends upon age at exposure and age at observation for risk. Using dose-response models based on committee reports published by the National Research Council and the National Institutes of Health, we project that, during the lifetimes of members of the MI population potentially exposed to ionizing radiation from weapons test fallout deposited during the testing period (1948-1958) and from residual radioactive sources during the subsequent 12 y (1959-1970), perhaps 1.6% (with 90% uncertainty range 0.4% to 3.4%) of all cancers might be attributable to fallout-related radiation exposures. By sub-population, the projected proportion of cancers attributable to radiation from fallout from all nuclear tests conducted in the Marshall Islands is 55% (28% to 69%) among 82 persons exposed in 1954 on Rongelap and Ailinginae, 10% (2.4% to 22%) for 157 persons exposed on Utrik, and 2.2% (0.5% to 4.8%) and 0.8% (0.2% to 1.8%), respectively, for the much larger populations exposed in mid-latitude locations including Kwajalein and in southern locations including Majuro. By cancer type, point estimates of attributable risk varied, by location, between 12% and 95% for thyroid cancer, between 2% and 78% for leukemia, and between 0.8% and 55% for all cancers combined. The largest projected risks pertain to the Rongelap Island community and the lowest risks pertain to the populations resident on the southern-most atolls. While the projected cancer risks are smaller than those estimated by the National Cancer Institute in a more simplistic analysis conducted in 2004, these estimates of cancer risk are the best available as they are based on the most detailed dose reconstruction to date and comprehensively include populations at all locations and dose contributions from all nuclear tests.

Microsatellite instability in radiation-induced murine tumours; influence of tumour type and radiation quality.

PURPOSE: To investigate microsatellite instability (MSI) in radiation-induced murine tumours, its dependence on tissue (haemopoietic, intestinal, mammary, brain and skin) and radiation type. MATERIALS AND METHODS: DNA from spontaneous, X-ray or neutron-induced mouse tumours were used in Polymerase Chain Reactions (PCR) with mono- or di-nucleotide repeat markers. Deviations from expected allele size caused by insertion/deletion events were assessed by capillary electrophoresis. RESULTS: Tumours showing MSI increased from 16% in spontaneously arising tumours to 23% (P = 0.014) in X-ray-induced tumours and rising again to 83% (P << 0.001) in neutron-induced tumours. X-ray-induced Acute Myeloid Leukaemias (AML) had a higher level of mono-nucleotide instability (45%) than di-nucleotide instability (37%). Fifty percent of neutron-induced tumours were classified as MSI-high for mono-nucleotide markers and 10% for di-nucleotide markers. Distribution of MSI varied in the different tumour types and did not appear random. CONCLUSIONS: Exposure to ionising radiation, especially neutrons, promotes the development of MSI in mouse tumours. MSI may therefore play a role in mouse radiation tumourigenesis, particularly following high Linear Energy Transfer (LET) exposures. MSI events, for a comparable panel of genome-wide markers in different tissue types, were not randomly distributed throughout the genome.

[But...was there ever a Clark classification of melanomas?]. / Pero...hubo alguna vez una clasificación de Clark de los melanomas?

For the past 40 years, the Clark classification of cutaneous melanoma has been accepted and used by the vast majority of dermatologists and pathologists throughout the world. However,after careful rereading of the most relevant articles by Clark and his collaborators, we can affirm that the classification was only ever of passing validity. Today, the possible morphological differences between one case of cutaneous melanoma and another are of no proven prognostic implication. In addition, the morphological differences that can be found are much more closely related to the different localization that to the tumor itself.

Gene expression profiling distinguishes between spontaneous and radiation-induced rat mammary carcinomas.

The ability to distinguish between spontaneous and radiation-induced cancers in humans is expected to improve the resolution of estimated risk from low dose radiation. Mammary carcinomas were obtained from Sprague-Dawley rats that were either untreated (n = 45) or acutely gamma-irradiated (1 Gy; n = 20) at seven weeks of age. Gene expression profiles of three spontaneous and four radiation-induced carcinomas, as well as those of normal mammary glands, were analyzed by microarrays. Differential expression of identified genes of interest was then verified by quantitative polymerase chain reaction (qPCR). Cluster analysis of global gene expression suggested that spontaneous carcinomas were distinguished from a heterogeneous population of radiation-induced carcinomas, though most gene expressions were common. We identified 50 genes that had different expression levels between spontaneous and radiogenic carcinomas. We then selected 18 genes for confirmation of the microarray data by qPCR analysis and obtained the following results: high expression of Plg, Pgr and Wnt4 was characteristic to all spontaneous carcinomas; Tnfsf11, Fgf10, Agtr1a, S100A9 and Pou3f3 showed high expression in a subset of radiation-induced carcinomas; and increased Gp2, Areg and Igf2 expression, as well as decreased expression of Ca3 and non-coding RNA Mg1, were common to all carcinomas. Thus, gene expression analysis distinguished between spontaneous and radiogenic carcinomas, suggesting possible differences in their carcinogenic mechanism.

Radiation-induced second malignancies.

There have been significant improvements in cancer treatment in the last few decades. The use of radiation in the treatment of cancer is widespread and has increased. Up to 40% of cancer pts will receive radiotherapy as part of their management. More successful treatment has meant improved survival rates, but conversely patients are living longer and encountering more treatment-induced complications. The development of a second primary malignancy, often many years later, is one of the more sinister complications. The American National Cancer Institute published data in 2006 reporting that 'Cancer survivors constitute 3.5% of the US population' but that 'second malignancies among high risk groups now accounts for 16% of all cancer incidence. The timescale between completion of the radiotherapy and the development of a second malignancy, known as the latent period, can vary widely from as little as 5 years up to 50 years later. In this report we present three cases of radiation-induced second malignancies seen in the Palliative Care setting and then give an overview of radiation induced second malignancies, looking at the aetiology, genetics and the palliative care implications for these patients.

A radiation-induced gene signature distinguishes post-Chernobyl from sporadic papillary thyroid cancers.

We investigated selected gene targets to differentiate radiation-induced papillary thyroid cancers (PTCs) from other etiologies. Total RNA was isolated from 11 post-Chernobyl PTCs and 41 sporadic PTCs characterized by a more aggressive tumor type and lacking a radiation exposure history. RNA from 10 tumor samples from both groups was pooled and hybridized separately on a whole genome microarray for screening. Then 92 selected gene targets were examined quantitatively on each tumor sample using an RTQ-PCR-based low-density array (LDA). Screening for more than fivefold differences in gene expression between the groups by microarray detected 646 up-regulated and 677 down-regulated genes. Categorization of these genes revealed a significant (P < 0.0006) over-representation of the number of up-regulated genes coding for oxidoreductases, G-proteins and growth factors, while the number of genes coding for immunoglobulin appeared to be significantly down-regulated. With the LDA, seven genes (SFRP1, MMP1, ESM1, KRTAP2-1, COL13A1, BAALC and PAGE1) made a complete differentiation between the groups possible. Gene expression patterns known to be associated with a more aggressive tumor type in older patients appeared to be more pronounced in post-Chernobyl PTC, thus underlining the known aggressiveness of radiation-induced PTC. Seven genes were found that completely distinguished post-Chernobyl (PTC) from sporadic PTC.