Managing Injuries of the Neck Trial (MINT) : design of a randomised controlled trial of treatments for whiplash associated disorders

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised

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

Relationships between Levels of Serum IgE, Cell-Bound IgE, and IgE-Receptors on Peripheral Blood Cells in a Pediatric Population

Background: Elevated serum immunoglobulin (Ig) E is a diagnostic marker of immediate-type allergic reactions. We hypothesize that serum IgE does not necessarily reflect total body IgE because in vivo IgE can be bound to cell surface receptors such as FcεRI and FcεRII (CD23). The aim of this study was to analyze the relationships between levels of serum IgE, cell-bound IgE, and IgE-receptors on peripheral blood cells in a pediatric population. Methodology: Whole blood samples from 48 children (26 boys, 22 girls, mean age 10,3±5,4 years) were analyzed by flow cytometry for FcεRI, CD23, and cell-bound IgE on dendritic cells (CD11c+MHC class II+), monocytes (CD14+), basophils (CD123+MHC class II-) and neutrophils (myeloperoxidase+). Total serum IgE was measured by ELISA and converted into z-units to account for age-dependent normal ranges. Correlations were calculated using Spearman rank correlation test. Principal Findings: Dendritic cells, monocytes, basophils, and neutrophils expressed the high affinity IgE-receptor FcεRI. Dendritic cells and monocytes also expressed the low affinity receptor CD23. The majority of IgE-receptor positive cells carried IgE on their surface. Expression of both IgE receptors was tightly correlated with cell-bound IgE. In general, cell-bound IgE on FcεRI+ cells correlated well with serum IgE. However, some patients carried high amounts of cell-bound IgE despite low total serum IgE levels. Conclusion/Significance: In pediatric patients, levels of age-adjusted serum IgE, cell-bound IgE, and FcεRI correlate. Even in the absence of elevated levels of serum IgE, cell-bound IgE can be detected on peripheral blood cells in a subgroup of patients

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

The investigation of chromosomal aberrations in adrenocortical tumours has been limited by the difficulties of applying classical cytogenetics to tumours with low levels of proliferation. We have therefore applied the technique of interphase cytogenetics to paraffin-embedded archival specimens of 14 adrenocortical adenomas and 13 carcinomas. Hybridizations were performed using centromere-specific probes to chromosomes 3, 4, 9, 17, 18 and X, which have been shown to be altered in other types of tumours. Chromosomal imbalance was defined on the basis of changes in both chromosome index (CI) and signal distribution (SD). Where only one of these was altered, this was classified as a tendency to gain or loss. On the basis of the analysis of optimal hybridizations, carcinomas showed gains in all chromosomes studied, five of nine showing gains in multiple chromosomes. Gains were most common in chromosomes 3, 9 and, in particular X, eight of 11 showing gain, and one a tendency to gain. Chromosomal gain was seen less commonly in adenomas, but again chromosomes 3, 9 and X were involved. Losses were infrequent, only one carcinoma showing loss of chromosome 18, and adenomas showing a tendency to loss of chromosomes 4 (two cases), 17 (one case) and 18 (two cases). Our data suggest that changes in chromosomes 3, 9 and X are early events in adrenocortical tumorigenesis, and that there is increasing chromosomal instability with tumour progression. © 1999 Cancer Research Campaig

Family eczema-history in 2-year olds with eczema; a prospective, population-based study. The PACT-study, Norway

<p>Abstract</p> <p>Background</p> <p>A maternal line of inheritance regarding eczema has been described in several studies, whereas others find associations to both a maternal as well as a paternal line of inheritance. When studying family history of eczema symptoms, cohort studies including siblings are rare. Time point for assessing family eczema-history could be of importance when studying the associations between family eczema-history and children with eczema, as parents with unaffected children may not recall mild symptoms in other siblings or their own disease history. We therefore aimed to study the associations between reported eczema in mother, father and siblings and reported eczema in index child where information on family history was collected at two different ages of index child.</p> <p>Methods</p> <p>Parents/children participating in The Prevention of Allergy among Children in Trondheim (PACT) study were given questionnaires on reported eczema symptoms in mother, father and siblings at 6 weeks and 1 year. When index child was 2 years of age, a detailed questionnaire on different health issues with emphasize on different allergy related disorders were filled in.</p> <p>Results</p> <p>Both maternal and paternal reports on eczema were significantly associated with eczema in index child. Reporting family eczema-history at 1 year (N = 3087), "eczema sibling only" [adjusted odds ratio (aOR) = 3.13 (2.27-4.33)] as well as all other family-groups containing siblings with eczema were strongly associated with eczema 2 years. When family eczema-history was reported at 6 weeks (N = 2657), reporting of "eczema sibling only" was not associated to reported eczema at 2 years in index child [aOR = 1.31 (0.77-2.23)].</p> <p>Conclusions</p> <p>Having sibling(s) with eczema strengthened the associations between maternal and paternal reports on eczema with eczema in index child only when exposure was reported at 1 year. These findings indicate that results from questionnaires-based studies of family eczema-history depend on whether or not index child has yet developed eczema.</p> <p>Trial registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN28090297">ISRCTN28090297</a></p

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1–2, Ki-674; n=25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/ depot 120mg was independent of NLRs (P>0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis

Assessment of the role of transcript for GATA-4 as a marker of unfavorable outcome in human adrenocortical neoplasms

BACKGROUND: Malignant neoplasia of the adrenal cortex is usually associated with very poor prognosis. When adrenocortical neoplasms are diagnosed in the early stages, distinction between carcinoma and adenoma can be very difficult to accomplish, since there is yet no reliable marker to predict tumor recurrence or dissemination. GATA transcription factors play an essential role in the developmental control of cell fate, cell proliferation and differentiation, organ morphogenesis, and tissue-specific gene expression. Normal mouse adrenal cortex expresses GATA-6 while its malignant counterpart only expresses GATA-4. The goal of the present study was to assess whether this reciprocal change in the expression of GATA factors might be relevant for predicting the prognosis of human adrenocortical neoplasms. Since human adrenal cortices express luteinizing hormone (LH/hCG) receptor and the gonadotropins are known to up-regulate GATA-4 in gonadal tumor cell lines, we also studied the expression of LH/hCG receptor. METHODS: We conducted a study on 13 non-metastasizing (NM) and 10 metastasizing/recurrent (MR) tumors obtained from a group of twenty-two adult and pediatric patients. The expression of GATA-4, GATA-6, and LH/hCG receptor (LHR) in normal and tumoral human adrenal cortices was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR) complemented by dot blot hybridization. RESULTS: Messenger RNA for GATA-6 was detected in normal adrenal tissue, as well as in the totality of NM and MR tumors. GATA-4, by its turn, was detected in normal adrenal tissue, in 11 out of 13 NM tumors, and in 9 of the 10 MR tumors, with larger amounts of mRNA found among those presenting aggressive clinical behavior. Transcripts for LH receptor were observed both in normal tissue and neoplasms. A more intense LHR transcript accumulation was observed on those tumors with better clinical outcome. CONCLUSION: Our data suggest that the expression of GATA-6 in human adrenal cortex is not affected by tumorigenesis. GATA-4 expression is more abundant in MR tumors, while NM tumors express more intensely LHR. Further studies with larger cohorts are needed to test whether relative expression levels of LHR or GATA-4 might be used as prognosis predictors

Heterogeneous activation of the TGFβ pathway in glioblastomas identified by gene expression-based classification using TGFβ-responsive genes

<p>Abstract</p> <p>Background</p> <p>TGFβ has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFβ overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFβ signaling to gain a comprehensive view of TGFβ activation in large cohorts of human glioma patients.</p> <p>Methods</p> <p>TGFβ activation in mammalian cells leads to a transcriptional program that typically affects 5–10% of the genes in the genome. To systematically examine the status of TGFβ activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFβ stimulation from tissue culture and <it>in vivo </it>animal studies. These genes were used to examine the status of TGFβ activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets.</p> <p>Results</p> <p>Unsupervised and supervised classification using the TGFβ-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFβ activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFβ activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFβ activation, while the rest showed a weak TGFβ transcriptional response.</p> <p>Conclusion</p> <p>Our findings suggest heterogeneous TGFβ activation in glioblastomas, which may cause potential differences in responses to anti-TGFβ therapies in these two distinct subgroups of glioblastomas patients.</p

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-β2 (TGF-β2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-β2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-β2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-β2 and inhibited by TGF-β2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-β domain of versican was able to reverse the effect of TGF-β2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-β2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1