Opting into breast screening over the age of 70 years: seeking evidence to support informed choice.

AIM: To provide evidence specific to the Scottish population regarding the risk-benefit balance of women >70 years opting into continued breast screening, which may be used as a basis for patient information documentation. MATERIALS AND METHODS: The present study consisted of a parallel, retrospective data analysis of breast cancer mortality data for breast cancer cases diagnosed between 2009 and 2013 (n=22,013) followed up to 31/12/18, and breast screening programme data from 2010 and 2015 (n=47,235). Screening outcome measures included recall for assessment, oncome of assessment, and tumour features. Tumours were classified as high, intermediate, or low risk according to grade and presence of invasion. Mortality data were linked to age at diagnosis and cause of death was recorded. RESULTS: The proportion of all deaths due breast cancer is inversely related to age at diagnosis. From 77 years, women are more likely to die with breast cancer, than directly due to breast cancer. Mammographic screening accurately identifies breast cancer in older women; however, many of the cancers detected were considered intermediate or low risk. CONCLUSIONS: Harms may outweigh the benefits of continued breast screening in older women. This information should be available to all older women.

Maternal high-fat diet impacts endothelial function in nonhuman primate offspring.

OBJECTIVE: The link between maternal under-nutrition and cardiovascular disease (CVD) in the offspring later in life is well recognized, but the impact of maternal over-nutrition on the offspring's cardiovascular function and subsequent risk for CVD later in life remains unclear. Here, we investigated the impact of maternal exposure to a high-fat/calorie diet (HFD) during pregnancy and early postnatal period on endothelial function of the offspring in a nonhuman primate model. METHODS: Offspring, naturally born to either a control (CTR) diet (14% fat calories) or a HFD (36% fat calories) consumption dam, were breast-fed until weaning at about 8 months of age. After weaning, the offspring were either maintained on the same diet (CTR/CTR, HFD/HFD), or underwent a diet switch (CTR/HFD, HFD/CTR). Blood samples and arterial tissues were collected at necropsy when the animals were about 13 months of age. RESULTS: HFD/HFD juveniles displayed an increased plasma insulin level and glucose-stimulated insulin secretion in comparison with CTR/CTR. In abdominal aorta, but not the renal artery, acetylcholine-induced vasorelaxation was decreased remarkably for HFD/HFD juveniles compared with CTR/CTR. HFD/HFD animals also showed a thicker intima wall and an abnormal vascular-morphology, concurrent with elevated expression levels of several markers related to vascular inflammation and fibrinolytic function. Diet-switching animals (HFD/CTR and CTR/HFD) displayed modest damage on the abdominal vessel. CONCLUSION: Our data indicate that maternal HFD exposure impairs offspring's endothelial function. Both early programming events and postweaning diet contribute to the abnormalities that could be reversed partially by diet intervention.

Plasticity of neuroblastoma tumor cells to differentiate along a fetal adrenal ganglionic lineage predicts for improved patient survival.

We have recently presented a model of human adrenal medullary histogenesis that incorporates all neural crest-derived lineages (chromaffin, sustentacular, and ganglionic) known to compose this tissue. To determine if neuroblastomas correspond to the arrested maturation of embryonal adrenal medullary cells, we evaluated the expression of adrenal medullary developmental markers in 81 neuroblastoma tumors. We found that patterns of chromaffin-related gene expression in these tumors correlated exactly with the patterns observed during maturation of adrenal medullary cells (P2 < 10(-5). In a multivariate Cox proportional hazards analysis of developmental marker expression and other well-recognized prognostic variables, evidence of maturation along a fetal ganglionic lineage, as monitored by HNK-1 immunoreactivity (relative risk of 6.42, P2 = 0.0001), and age at diagnosis (relative risk of 5.05, P2 = 0.0042) were independent and significant prognostic indicators of patient survival. These studies demonstrate that neuroblastomas correspond to embryonal adrenal medullary cells arrested at recognizable stages during development, and that evidence of maturation along a fetal ganglionic lineage appears to have major importance in predicting patient survival.

Insulin-like growth factor II-mediated proliferation of human neuroblastoma.

Neuroblastoma is an embryonal tumor that typically arises in cells of the developing adrenal medulla. IGF-II mRNA is expressed at high levels in the adrenal cortex before birth but it is not detectable until after birth in the adrenal medulla. Neuroblastoma cell lines corresponding to early adrenal medullary precursors did not express IGF-II, although all three cell lines we tested were growth stimulated by IGF-II. Cell lines corresponding to more mature adrenal medullary cells expressed IGF-II, and one, SK-N-AS, grows by an IGF-II autocrine mechanism (J. Clin. Invest. 84:829-839) El-Badry, Romanus, Helman, Cooper, Rechler, and Israel. 1989. An examination of human neuroblastoma tumor tissues for IGF-II gene expression using in situ hybridization histochemistry revealed that IGF-II is expressed by tumor cells in only 5 of 21 neuroblastomas, but is detectable in cells of nonmalignant tissues including adrenal cortical cells, stromal fibroblasts, and eosinophils in all 21 tumors. These findings indicate that IGF-II may function as an autocrine growth factor for some neuroblastomas and as a paracrine growth factor for others. They suggest that the growth regulatory pathways utilized by neuroblastoma mimic those used in the precursor cell type from which individual tumors arise.

Source of increased ferritin in neuroblastoma: studies with concanavalin A-sepharose binding.

Serum ferritin is present in two forms--a glycosylated form that results from active secretion by cells and a nonglycosylated form that is directly released by damaged cells. Glycosylated ferritin binds to concanavalin A (Con A) through the glucose and/or mannose residues of the molecule. Patients with neuroblastoma frequently present at diagnosis with abnormally elevated levels of serum ferritin. The ferritin levels will, however, return to normal with clinical remission, suggesting that the tumor is the origin of the elevated ferritin. With the use of a Con A binding assay, an investigation was made as to whether the increased levels of serum ferritin at diagnosis in neuroblastoma patients resulted from active secretion by the tumor or were the consequence of direct release of ferritin from damaged tissue. Serum samples were collected at diagnosis from 36 children with neuroblastoma and from 16 normal healthy subjects. Tissue ferritins were purified from normal human liver, placenta, HeLa cells, human neuroblastoma, and hepatoma cells grown in culture. Serum and tissue ferritins were measured before and after binding with Con A. Sixty-three percent of serum ferritin from neuroblastoma patients and 66% of serum ferritin from normal subjects were bound to Con A, suggesting that they were glycosylated and were likely to have been secreted. On the other hand, only 28% of tissue ferritin were bound to Con A. Furthermore, most patients showed abnormally elevated levels of serum ferritin, and 63% of these ferritins were bound to Con A. These results are compatible with the hypothesis that much of the elevated ferritin in sera of patients with neuroblastoma seen at diagnosis is the result of secretion of ferritin by the tumor.

Incidence of childhood cancer: experience of a decade in a population-based registry.

Incidence rates of cancer among children aged 0-14 for the period 1970-79 have been generated with the use of data from the Greater Delaware Valley (GDV) Pediatric Tumor Registry. This population-based registry covers a 31-county area and has a pediatric base population of 2 million. During the period, approximately 2,300 cases of childhood cancer were diagnosed in the region. Incidence rates for all histologic types combined are similar to rates from other large surveys conducted in the United States and Western Europe. However, certain histology-specific rates in the GDV vary by race. In the GDV nonwhites relative to whites have higher rates of Wilms' tumor, soft tissue sarcomas other than rhabdomyosarcoma, and retinoblastoma. These contrasts are supported by surveys in African populations showing relatively higher rates of these tumors among African black children. GDV whites exceed nonwhites in incidence of acute leukemia, neuroblastoma, and Ewing's sarcoma. African black children also experience low rates of these tumors. The frequency of central nervous system tumors is similar for GDV whites and nonwhites, despite reports of a rarity of these neoplasms in African blacks. Variations in incidence rates reveal population subgroups with particular tumor susceptibilities and may provide clues as to the relative influence of heredity and environment on patterns observed.

Lack of influence of T-cell marker and importance of mediastinal mass on the prognosis of acute lymphocytic leukemias of childhood.

One hundred consecutive new cases of acute lymphocytic leukemia (ALL) were studied in patients that were 4 months to 16 years of age when admitted to The Children's Hospital of Philadelphia. Various prognostic factors were examined and related to the duration of the first remission. These factors included lymphoblast surface markers, age at diagnosis, sex, race, initial white blood counts (WBC), presence of mediastinal mass, degree of hepatosplenomegaly, and lymph node size. Classification by lymphoblast surface markers showed 22 T-cell, 71 null cell, and 3 B-cell leukemias; 3 cases were unclassifiable and 1 had both T- and B-cell markers. Statistical analysis indicated that stratification by presence or absence of mediastinal mass was necessary. Most patients with mediastinal masses, 5 of thymus and 4 of the non-thymus type, fared poorly with a median duration of continuous complete remission of less than 12 months as compared with greater than 48 months for those without such masses. The most satisfactory model to estimate remission duration in children without mediastinal masses was dependent upon initial WBC, sex, race, and surface markers. Low WBC, white race, female sex, and T-cell markers in patients without mediastinal masses were associated with a favorable prognosis. The findings suggest that patients with mediastinal masses need special therapy and that T-cell ALL without a mediastinal masses need special therapy and that T-cell ALL without a mediastinal mass does not carry a poorer prognosis than does null cell ALL.

Studies of parents of children with acute leukemia.

In a case-control study, 70 mothers and 24 fathers of children with acute leukemia (AL) were compared with 70 mothers and 24 fathers of normal children. Three significant differences (p smaller than 0.05) were found when 35 factors were compared among the mother pairs and one difference among the father pairs. Mothers of children with AL, though alike in most respects to their matched controls, had a significantly lower number of monocytes than their controls. This was a new observation. The mothers of the children with AL also had higher levels of gamma-globulin, IgA, and IgG (Philadelphia only), which confirmed previous observations. The fathers and mothers had higher levels of basophils. These findings direct attention to the immune systems, particularly the mononuclear cells, of the parents of children with AL, as a focus for further studies on the etiology and pathogenesis of childhood leukemia.

Models to predict outcome from childhood neuroblastoma: the role of serum ferritin and tumor histology.

We report on the development of three multiple logistic regression models to predict death from childhood neuroblastoma in patients treated without bone marrow transplantation. The models have been developed using a data set of 125 patients for whom age, stage, serum ferritin, and/or histology were available from diagnosis. Seventy-seven patients had all four variables recorded at diagnosis, 34 had age, stage, and serum ferritin, and 14 had age, stage, and histology. Minimum time from diagnosis for all patients was 3 years. The four-variable (full) model showed a predictive value positive rate (or 1 - the false positive rate) of 91.3% and a predictive value negative rate (or 1 - the false negative rate) of 94.4%. Survival curves, based on derived "good" and "poor" prognosis, were constructed for the full model of 77 patients and for the same patients using subset models either without ferritin or without histology. Correcting for prognostic factors noted at diagnosis, no time trend could be identified over the study period. Point estimates for the probability of death in all three models are displayed in graphical form. The results suggest that serum ferritin and tumor histology at diagnosis have independent prognostic significance and that patient outcome in neuroblastoma can be very accurately predicted with a four-variable model. Such information will help sort patients into good and poor prognosis for bone marrow transplant and intensive chemotherapy protocol triage and will help evaluate the efficacy of future therapeutic innovations.

Serum ferritin as a guide to therapy in neuroblastoma.

Elevated serum ferritin levels without a corresponding increase in tissue iron storage have been observed in patients with certain cancers. Increased synthesis of ferritin by cancer cells has also been reported. In order to see whether similar phenomena occurred in patients with neuroblastoma, we have screened serum ferritin levels in 58 children with neuroblastoma by counterelectrophoresis using antibody to human ferritin. Increased ferritin levels in serum, positive by counterelectrophoresis (greater than or equal to 400 ng/ml), correlated well with the presence of active disease (p less than 0.001 by Fisher's exact 2 X 2 test). A longitudinal study of serum ferritin levels in 34 of the 58 patients showed the same association of elevated serum ferritin with active disease; a return of ferritin levels to the normal ranges coincided with remission. Primary neuroblastoma tumors and cells from neuroblastoma cell lines contained ferritins with the electrophoretic characteristics different from normal liver ferritin. Supernatant fluids from six neuroblastoma cell lines grown in culture also contained ferritin. These findings suggest that the increased ferritin in the serum of patients is derived from the tumor. The serum ferritin level could be used as indicator of disease activity and as a guide to therapy.