TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

Effectiveness of return-to-work interventions for disabled people: a systematic review of government initiatives focused on changing the behaviour of employers

Background: OECD countries over the past two decades have implemented a range of labour market integration initiatives to improve the employment chances of disabled and chronically ill individuals. This article presents a systematic review and evidence synthesis on effectiveness of government interventions to influence employers’ employment practices concerning disabled and chronically ill individuals in five OECD countries. A separate paper reports on interventions to influence the behaviour of employees. Methods: Electronic and grey literature searches to identify all empirical studies reporting employment effects and/or process evaluations of government policies aimed at changing the behaviour of employers conducted between 1990 and 2008 from Canada, Denmark, Norway, Sweden and the UK. Results: Few studies provided robust evaluations of the programmes or their differential effects and selection of participants into programmes may distort the findings of even controlled studies. A population-level effect of legislation to combat discrimination by employers could not be detected. Workplace adjustments had positive impacts on employment, but low uptake. Financial incentives such as wage subsidies can work if they are sufficiently generous. Involving employers in return-to-work planning can reduce subsequent sick leave and be appreciated by employees, but this policy has not been taken up with the level of intensity that is likely to make a difference. Some interventions favour the more advantaged disabled people and those closer to the labour market. Conclusions: Future evaluations need to pay more attention to differential impact of interventions, degree of take-up, non-stigmatizing implementation and wider policy context in each country