Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-κB (NF-κB) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-κB activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1ß, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tnfrsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-κB activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis.

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CitationUp to now chemotherapy has not shown to improve survival in these patients. The outcome of Radiation Therapy (RT) in combination with Nimotuzumab is shown in the present report. Material and Methods: 28 children and adolescents were included between Jan/2009 and Dec/2012 with the diagnosis of BSG and follow-up till January 2015. All patients had Diffuse infiltrative Pontine Gliomas (DIPG) and were irradiated with a dose ranging from 54 to 59.6 Gy at the National Oncology and Radiobiology Institute in Havana, Cuba. Three patients were planned with IMRT and 25 with 3D Conformal RT. Nimotuzumab was indicated at the dose of 150 mg/m 2 weekly during the time of RT treatment, then every 15 days during 8 weeks and finally monthly for 1 year. Univariate and multivariate Cox regression models and Kaplan Meier survival were analyzed to evaluate the survival. Results: Median age at diagnosis was 7 years (range 3-18 years old), median overall survival was 17.3 months (95% CI 14.0-20.5 ) since the beginning of the treatment and the accumulated survival at 5 years of treatment was 42,9%. There was balance in sex, age and dosage of RT in the population. Addition of Nimotuzumab to RT was safe. Conclusions: The combination of Radiotherapy and Nimotuzumab were well tolerated in this brainstem tumours patient's series.

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