Is inflammatory bowel disease an independent and disease specific risk factor for thromboembolism?

Background: Patients with inflammatory bowel disease (IBD) are thought to be at increased risk of venous thromboembolism (TE). However, the extent of this risk is not known. Furthermore, it is not known if this risk is specific for IBD or if it is shared by other chronic inflammatory diseases or other chronic bowel diseases. Aims: To compare the risk of TE in patients with IBD, rheumatoid arthritis, and coeliac disease with matched control subjects. Patients and methods: Study subjects answered a questionnaire assessing the history of TE, any cases of which had to be confirmed radiologically. A total of 618 patients with IBD, 243 with rheumatoid arthritis, 207 with coeliac disease, and 707 control subjects were consecutively included. All three patient groups were compared with control subjects matched to the respective group by age and sex. Results: Thirty eight IBD patients (6.2%) had suffered TE. This was significantly higher compared with the matched control population with only 10 cases reported (1.6%) (p<0.001; odds ratio (OR) 3.6 (95% confidence interval (CI) 1.7–7.8)). Five patients with rheumatoid arthritis (2.1%) had suffered TE compared with six subjects (2.5%) in the control population matched to patients with rheumatoid arthritis (NS; OR 0.7 (95% CI 0.2–2.9)). TE had occurred in two patients with coeliac disease (1%) compared with four subjects (1.9%) in the control population matched to the coeliac disease group (NS; OR 0.4 (95% CI 0.1–2.5)). In 60% of TE cases in the IBD group, at least one IBD specific factor (active disease, stenosis, fistula, abscess) was present at the time TE occurred. Conclusions: IBD is a risk factor for TE. It seems that TE is a specific feature of IBD as neither rheumatoid arthritis, another chronic inflammatory disease, nor coeliac disease, another chronic bowel disease, had an increased risk of TE

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15–25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR(1,2) inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR(1,2) in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR(1,2) inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR(1,2) inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies