Alternative models for measuring temporal trends in incidence and mortality rates

The average percent change (APC) is often used to measure temporal trends. Under the assumption of linearity on the logarithmic scale, the APC is estimated by using a generalized linear model. A serious limitation of least-squares type estimators is their sensitivity to outliers. The goal of this study is two-fold: firstly, we propose a robust and easy-to-compute measure of the temporal trend based on the median of the rates (median percent change - MPC), rather than their mean; secondly, we investigate the performance of several models for estimating the rate of change when some of the most common model assumptions are violated. We provide some general guidance on the practices of the estimation of temporal trends when using different models under different circumstances. Also, we analyzed an English cancer registration dataset to illustrate the proposed method. The MPC provides a robust alternative to APC. We believe that, as a good practice, both APC and MPC should be presented when sensitivity issues arise. The modelling of data subsets, in any case, should reflect the peculiarity of the process from where the dataset has originated

A parameterization of convective dust storms for models with mass-flux convective schemes

Cold pool outflows, generated by downdrafts from moist convection, can generate strong winds and therefore uplift of mineral dust. These so-called “haboob” convective dust storms occur over all major dust source areas worldwide and contribute substantially to emissions in northern Africa, the world’s largest source. Most large-scale models lack convective dust storms, because they do not resolve moist convection, relying instead on convection schemes. We suggest a parameterization of convective dust storms to account for their contribution in such large-scale models. The parameterization is based on a simple conceptual model, in which the downdraft mass flux from the convection scheme spreads out radially in a cylindrical cold pool. The parameterization is tested with a set of Unified Model runs for June and July 2006 over West Africa. It is calibrated with a convection-permitting run, and applied to a convection-parameterized run. The parameterization successfully produces the extensive area of dust-generating winds from cold pool outflows over the southern Sahara. However, this area extends farther to the east and dust generating winds occur earlier in the day than in the convection-permitting run. These biases are due to biases in the convection scheme. It is found that the location and timing of dust-generating winds are weakly sensitive to the parameters of the conceptual model. The results demonstrate that a simple parameterization has the potential to correct a major and long-standing limitation in global dust models

Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization

We have examined 11 cases of childhood adrenocortical tumours for copy number changes using comparative genomic hybridization (CGH). The changes seen are highly consistent between cases, and are independent of tumour type (carcinoma versus adenoma) or the presence of a germline TP53 mutation. The regions of chromosomal gain and loss identified in this study indicate the location of genes that are potentially important in the development and progression of childhood adrenocortical tumours. Finally, the copy number changes identified in childhood tumours are distinctly different to those seen in adult cases (Kjellman et al (1996) Cancer Res56: 4219–4223), and we propose that this indicates that childhood tumours are of embryonal origin. © 1999 Cancer Research Campaig

Endo180 (MRC2) antibody-drug conjugate for the treatment of sarcoma.

Although the 5-year survival rates for sarcoma patients have improved, the proportion of patients relapsing after first line treatment remains high and survival of patients with metastatic disease is dismal. Moreover, the extensive molecular heterogeneity of the multiple different sarcoma subtypes poses a substantial challenge to developing more personalized treatment strategies. From immunohistochemical staining of a large set of 625 human soft tissue sarcomas we demonstrate strong tumor cell staining of the Endo180 (MRC2) receptor in a high proportion of samples, findings echoed in gene expression datasets showing a significantly increased expression in both soft tissue and bone sarcomas compared to normal tissue. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate (ADC). An anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE via a cleavable linker, is rapidly internalized into target cells and trafficked to the lysosome for degradation, causing cell death specifically in Endo180 expressing sarcoma cell lines. In a sarcoma tumor xenograft model, the Endo180-vc-MMAE ADC, but not an Isotype-vc-MMAE control or the unconjugated Endo180 antibody, drives on target cytotoxicity resulting in tumor regression and a significant impairment of metastatic colonization of the lungs, liver and lymph nodes. These data, together with the lack of a phenotype in mice with an Mrc2 genetic deletion, provide pre-clinical proof-of-principle evidence for the future development of an Endo180-ADC as a therapeutic strategy in a broad range of sarcoma subtypes and, importantly, with potential impact both on the primary tumor and in metastatic disease

Survival from cancer in teenagers and young adults in England, 1979–2003

Cancer is the leading cause of disease-related death in teenagers and young adults aged 13–24 years (TYAs) in England. We have analysed national 5-year relative survival among more than 30 000 incident cancer cases in TYAs. For cancer overall, 5-year survival improved from 63% in 1979–84 to 74% during 1996–2001 (P<0.001). However, there were no sustained improvements in survival over time among high-grade brain tumours and bone and soft tissue sarcomas. Survival patterns varied by age group (13–16, 17–20, 21–24 years), sex and diagnosis. Survival from leukaemia and brain tumours was better in the youngest age group but in the oldest from germ-cell tumours (GCTs). For lymphomas, bone and soft tissue sarcomas, melanoma and carcinomas, survival was not significantly associated with age. Females had a better survival than males except for GCTs. Most groups showed no association between survival and socioeconomic deprivation, but for leukaemias, head and neck carcinoma and colorectal carcinoma, survival was significantly poorer with increasing deprivation. These results will aid the development of national specialised service provision for this age group and identify areas of clinical need that present the greatest challenges

Space-time clustering analyses of childhood acute lymphoblastic leukaemia by immunophenotype

Space-time clustering analyses of acute lymphoblastic leukaemia in children, by immunophenotype, were carried out using a population-based registry. Significant evidence was found of space-time clustering for cases of the precursor B-cell sub-type, in the childhood peak, based on time and location at birth

An infectious aetiology for childhood brain tumours? Evidence from space–time clustering and seasonality analyses

To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space–time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space–time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space–time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents