Contribution of Genetic Background to the Radiation Risk for Cancer and Non-Cancer Diseases in Ptch1+/- Mice.

Experimental mouse studies are important to gain a comprehensive, quantitative and mechanistic understanding of the biological factors that modify individual risk of radiation-induced health effects, including age at exposure, dose, dose rate, organ/tissue specificity and genetic factors. In this study, neonatal Ptch1+/- mice bred on CD1 and C57Bl/6 background received whole-body irradiation at postnatal day 2. This time point represents a critical phase in the development of the eye lens, cerebellum and dentate gyrus (DG), when they are also particularly susceptible to radiation effects. Irradiation was performed with γ rays (60Co) at doses of 0.5, 1 and 2 Gy, delivered at 0.3 Gy/min or 0.063 Gy/min. Wild-type and mutant mice were monitored for survival, lens opacity, medulloblastoma (MB) and neurogenesis defects. We identified an inverse genetic background-driven relationship between the radiosensitivity to induction of lens opacity and MB and that to neurogenesis deficit in Ptch1+/- mutants. In fact, high incidence of radiation-induced cataract and MB were observed in Ptch1+/-/CD1 mutants that instead showed no consequence of radiation exposure on neurogenesis. On the contrary, no induction of radiogenic cataract and MB was reported in Ptch1+/-/C57Bl/6 mice that were instead susceptible to induction of neurogenesis defects. Compared to Ptch1+/-/CD1, the cerebellum of Ptch1+/-/C57Bl/6 mice showed increased radiosensitivity to apoptosis, suggesting that differences in processing radiation-induced DNA damage may underlie the opposite strain-related radiosensitivity to cancer and non-cancer pathologies. Altogether, our results showed lack of dose-rate-related effects and marked influence of genetic background on the radiosensitivity of Ptch1+/-mice, supporting a major contribution of individual sensitivity to radiation risk in the population.

High incidence of medulloblastoma in Maori and Pacific populations in New Zealand.

In New Zealand from 1995-2010, the incidence of medulloblastoma at ages 1-19 years was significantly higher in Maori (relative risk 2.0) and in Pacific peoples (RR 2.1) than in New Zealand Europeans.

Infant brain tumors: incidence, survival, and the role of radiation based on Surveillance, Epidemiology, and End Results (SEER) Data.

PURPOSE: To evaluate the incidence of infant brain tumors and survival outcomes by disease and treatment variables. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results (SEER) Program November 2008 submission database provided age-adjusted incidence rates and individual case information for primary brain tumors diagnosed between 1973 and 2006 in infants less than 12 months of age. RESULTS: Between 1973 and 1986, the incidence of infant brain tumors increased from 16 to 40 cases per million (CPM), and from 1986 to 2006, the annual incidence rate averaged 35 CPM. Leading histologies by annual incidence in CPM were gliomas (13.8), medulloblastoma and primitive neuroectodermal tumors (6.6), and ependymomas (3.6). The annual incidence was higher in whites than in blacks (35.0 vs. 21.3 CPM). Infants with low-grade gliomas had the highest observed survival, and those with atypical teratoid rhabdoid tumors (ATRTs) or primary rhabdoid tumors of the brain had the lowest. Between 1979 and 1993, the annual rate of cases treated with radiation within the first 4 months from diagnosis declined from 20.5 CPM to <2 CPM. For infants with medulloblastoma, desmoplastic histology and treatment with both surgery and upfront radiation were associated with improved survival, but on multivariate regression, only combined surgery and radiation remained associated with improved survival, with a hazard ratio for death of 0.17 compared with surgery alone (p = 0.005). For ATRTs, those treated with surgery and upfront radiation had a 12-month survival of 100% compared with 24.4% for those treated with surgery alone (p = 0.016). For ependymomas survival was higher in patients treated in more recent decades (p = 0.001). CONCLUSION: The incidence of infant brain tumors has been stable since 1986. Survival outcomes varied markedly by histology. For infants with medulloblastoma and ATRTs, improved survival was observed in patients treated with both surgery and early radiation compared with those treated with surgery alone.

Multifocal desmoplastic medulloblastoma in an african-american child with nevoid basal cell carcinoma (gorlin) syndrome. Case report.

The authors present the case of a 2.5-year-old African-American boy with desmoplastic medulloblastoma (MB) and nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, an autosomal dominant disorder resulting from mutations in the patched (PTCH) gene that predisposes to neoplasias (including basal cell carcinomas [BCCs] and MB) and to widespread congenital malformations. The diagnosis of NBCCS was suspected based on the clinical examination, patient and family medical histories, and histopathological characteristics of the tumor. Radiotherapy was withheld. The diagnosis of NBCCS was confirmed by DNA testing, which revealed a novel mutation in the PTCH gene. This is the first report of an African-American child with MB diagnosed with NBCCS prior to radiotherapy. Although only a small number of patients with MB have NBCCS, the diagnosis must be considered because radiotherapy in such patients can lead to the formation of BCCs and other intracranial neoplasms within the irradiated field. This case emphasizes the importance of obtaining thorough family and patient medical histories and of carefully examining the patient and close relatives for signs of NBCCS to avoid the potentially devastating consequences of missing this diagnosis.

Pediatric brain tumors in non-Hispanics, Hispanics, African Americans and Asians: differences in survival after diagnosis.

BACKGROUND: Racial differences in survival for children with brain tumors have not been well studied, particularly in Hispanics and Asians. The objective of this study was to assess racial differences in survival of children with brain tumors, focusing on Hispanics, African Americans and Asians compared to Non-Hispanics. METHODS: Subjects identified through the SEER Program were 2799 children, < or =19 years old at diagnosis, newly diagnosed between 1973 and 1996 with primary, malignant brain tumors. Chi-square tests were used to evaluate prognostic variables by race. Kaplan-Meier models and Cox proportional hazards models were used to assess racial differences in overall survival and in survival by histological type of tumor. RESULTS: The distribution histological type of tumor varied significantly by race. Overall survival was similar for Hispanics, African Americans, Asians compared to Non-Hispanics, although trends of increased risk of death for the minority groups were noted when stratifying by histological type of tumor. CONCLUSIONS: Racial differences in survival could exist by histological type of tumor, but further work is necessary for a more complete understanding of these differences.

Trends in the incidence of primary intracranial tumors in Kumamoto, Japan.

BACKGROUND: The introduction of modern neuro-imaging techniques, as well as various environmental factors, have been changing the incidence and the proportions of the types of clinically diagnosed intracranial tumors. The aim of this study was to determine recent trends in the occurrence of primary intracranial tumors in the residents of Kumamoto Prefecture, Japan. METHODS: We surveyed 2129 patients who were diagnosed with primary intracranial tumors between 1989 and 1998, with histological diagnosis being obtained in 71% of the patients. RESULTS: Of the 2129 patients, 710 (33.3%) had meningiomas, 390 (18.3%) had pituitary adenomas, 315 (14.8%) had malignant gliomas, and 208 (9.8%) had schwannomas. The overall age-adjusted incidence rates were 10.97/100,000/year (males, 9.70; females, 11.86). One hundred and nine patients (5.1%) were younger than 15 years, and 480 patients (22.5%) were older than 70 years. The most common tumors in children were astrocytomas (37.6%), followed by germ-cell tumors (16.5%) and craniopharyngiomas (11.9%), medulloblastomas (11.0%), and ependymomas (4.6%). Meanwhile, the most common tumors in elderly residents were meningioma (51.7%), followed by malignant glioma (13.7%), pituitary adenoma (11.4%), schwannoma (7.7%), malignant lymphoma (4.6%), and astrocytoma (2.7%). The proportion of asymptomatic tumors increased, from 24.6% in 1989-1994 to 33.0% in 1995-1998; 169 (62.8%) were meningiomas, followed by pituitary adenomas (14.1%).

Descriptive epidemiology of primary cancer of the brain, cranial nerves, and cranial meninges in New Zealand, 1948-88.

We used New Zealand data on occurrence of different types of brain cancer to investigate: (i) a possible secular increase which has been seen worldwide and has generated considerable debate; (ii) possibly higher rates among Maori; and (iii) possibly higher risks related to social class and occupation. Data from the NZ Cancer Registry on the 5,684 brain cancers diagnosed among NZ residents from 1948-88 were used to study the pattern of occurrence by gender, age, race, calendar year, social class, occupation, and histology. Age-standardized brain-cancer incidence rates per 100,000 more than doubled over the 41-year period (from 2.9 to 6.9 in males and from 2.1 to 5.1 in females). A strong trend of increasing incidence with increasing social class is seen in males (Ptrend = 0.01). Among Maori, the proportion of all brain cancer that is medulloblastoma is four times that among non-Maori, and the proportion of all brain cancers that lack histologic confirmation is about 40 percent higher. Elevated risks are seen among: dairy farmers (odds ratio [OR] = 3.4, 95 percent confidence interval [CI] = 1.9-6.0); sheep handlers (OR = 2.7, CI = 1.4-5.3); livestock workers (OR = 3.8, CI = 1.7-8.4); and farm managers (OR = 3.2, CI = 1.4-7.2); as well as among electrical engineers (OR = 8.2, CI = 20-34.7); electricians (OR = 4.6, CI = 1.7-12.2); and other electrical workers. Brain cancer rates in NZ have increased steadily since 1948, but this increase has leveled off in the most recent five-year period. Although brain cancer rates are likely to be underestimated among the Maori, an excess of medulloblastoma is evident in this group.

Ethnic distribution of primary central nervous system tumors in Washington, DC, 1971 to 1985.

An ethnic analysis was made of 8947 cases of primary central nervous system (CNS) tumors seen at the Armed Forces Institute of Pathology (AFIP), Washington, DC, from 1971 to 1985. Results showed a slightly higher frequency of primary CNS tumors in whites than in blacks with a white:black case ratio of 9:1 against the white:black population ratio in the United States of 7.4:1. Gliomas appeared to be twofold more frequent in whites than in blacks with a white:black case ratio of 12.1:1. However, meningiomas and pituitary adenomas were more common in blacks with a white:black case ratio of 6.7:1 and 4.2:1, respectively. When these results were compared with the results of a previous identical study using similar materials collected at AFIP from 1958 to 1970, the relative paucity of gliomas and higher frequency of meningiomas and pituitary adenomas in American blacks is again confirmed, thus re-emphasizing the importance of genetic factors in the genesis of primary CNS tumors. The remarkable decreasing white:black case ratio of primary CNS tumors as a whole (9:1 compared with 13.7:1) since 1970 probably reflects the socioeconomic improvement of American blacks during the same period.

Racial patterns of childhood brain cancer by histologic type.

Racial patterns of childhood brain cancer by histologic type were studied using data from the Third National Cancer Survey and the Surveillance, Epidemiology, and End Results Program. Incidence rates for whites of all types combined and of astrocytic glioma and medulloblastoma were slightly higher than those for blacks. Proportionately more black than white cases of astrocytic glioma were diagnosed between the ages of 5-9 years; this difference corresponded to twofold-higher rates at ages of 0-4 and 10-14 years and similar rates at ages of 5-9 years among whites compared to rates among nonwhites. A real difference in age-incidence curves rather than diagnostic delay among blacks appeared to explain the differences. For medulloblastoma, the male-female rate ratio differed between whites (1.7) and blacks (1.0). Time trend analyses revealed statistically significant increases in medulloblastoma and glioma not otherwise specified (NOS) for incidences among blacks. The rate of microscopic confirmation was significantly higher among whites than among blacks, a difference apparently not explained by differences in the accessibility of tumors for biopsy. For avoidance of biased comparisons, differences in rates of microscopic confirmation and time trends for glioma NOS should be considered in studies of racial patterns of childhood brain cancer incidence by histologic type.