A gene expression signature for high-risk multiple myeloma.

There is a strong need to better predict the survival of patients with newly diagnosed multiple myeloma (MM). As gene expression profiles (GEPs) reflect the biology of MM in individual patients, we built a prognostic signature based on GEPs. GEPs obtained from newly diagnosed MM patients included in the HOVON65/GMMG-HD4 trial (n=290) were used as training data. Using this set, a prognostic signature of 92 genes (EMC-92-gene signature) was generated by supervised principal component analysis combined with simulated annealing. Performance of the EMC-92-gene signature was confirmed in independent validation sets of newly diagnosed (total therapy (TT)2, n=351; TT3, n=142; MRC-IX, n=247) and relapsed patients (APEX, n=264). In all the sets, patients defined as high-risk by the EMC-92-gene signature show a clearly reduced overall survival (OS) with a hazard ratio (HR) of 3.40 (95% confidence interval (CI): 2.19-5.29) for the TT2 study, 5.23 (95% CI: 2.46-11.13) for the TT3 study, 2.38 (95% CI: 1.65-3.43) for the MRC-IX study and 3.01 (95% CI: 2.06-4.39) for the APEX study (P<0.0001 in all studies). In multivariate analyses this signature was proven to be independent of the currently used prognostic factors. The EMC-92-gene signature is better or comparable to previously published signatures. This signature contributes to risk assessment in clinical trials and could provide a tool for treatment choices in high-risk MM patients.

Immediate pain sensation is less with subcutaneous epoietin-beta compared to subcutaneous darbepoietin-alpha.

Although immediate pain sensation at the injection site is reported by patients, only limited data on comparison of pain at the injection site between erythropoiesis stimulating agents are available. Therefore, we compared the effect of subcutaneous epoietin-beta on immediate pain sensation to that of subcutaneous darbepoietin-alpha in a double blind, randomized controlled study. Adult patients, aged 18 - 75 years, treated with peritoneal dialysis or with stage 4 chronic kidney disease who in our unit are treated with subcutaneous darbepoietin-alpha for renal anemia for at least 3 months, were eligible for the study. After informed consent, patients received on one day four subcutaneous injections, two in each upper leg, in a fixed sequence, blinded to the patient and blinded to the investigator. Injections contained in a random order single dose epoietin-beta (0,3 ml = 4000 IU), darbepoietin-alpha (0,5 ml = 20 microg) and volume matched saline 0.9% placebo injections. Immediately after the four injections, whilst remaining sitting, the subject was requested to fill out one pain scale (Visual Analogue Scale (VAS)) and to verbally evaluate the pain experience (Verbal Pain Score (VPS)). Finally, the subject was requested to rank the four injections from least to most painful (Treatment Ranking). A total of 42 patients (22 male) participated in the study with a mean age of 56.8 +/- 1.9 years. The average VAS was lower for epoietin-beta (26.8 +/- 4.5 mm) compared to darbepoietin-alpha (58.1 +/- 4.6 mm; p < 0.01). Mean VAS for epoietin-beta did not differ from that of the two placebo saline solutions (0,3 ml 26.3 +/- 4.4 mm; 0,5 ml 18.4 +/- 3.2 mm). Mean VAS for darbepoietin-alpha was significantly higher than placebo (both p < 0.01). Similar observations were obtained for VPS (mean for epoietin-beta 1,3 +/- 0.2 and for darbepoietin-alpha 2.9 +/- 0.2; p < 0.01) and Treatment Ranking (mean for epoietin-beta 2.0 +/- 0.2 and for darbepoietin-alpha 3.2 +/- 0.2; p < 0.01). From the results it can be concluded that subcutaneous epoietin-beta caused statistically significant less pain sensation immediately after injection compared to subcutaneous darbepoietin-alpha . The pain caused by subcutaneous epoietin-beta injection was similar to that caused by placebo control injections whereas subcutaneous darbepoietin-alpha injection was significantly more painful than subcutaneous placebo injections.

Endotoxin release and tumor necrosis factor formation during cardiopulmonary bypass.

Endotoxin, when released into the systemic circulation during cardiopulmonary bypass (CPB), might induce activation of plasmatic systems and blood cells during CPB, in addition to a material-dependent blood activation during CPB. However, the role of endotoxin in the development of this so-called whole-body inflammatory reaction in CPB is still unclear. We investigated the release of endotoxin into the systemic circulation in relation with the activation of the complement system and in particular the formation of tumor necrosis factor in 10 patients undergoing CPB. Immediately after the start of CPB the endotoxin concentrations increased significantly (p less than 0.01), accompanied by increases in C3a concentration (p less than 0.05). After release of the aortic cross-clamp, there was a second increase in endotoxin followed by a continuous increase in tumor necrosis factor, reaching a peak concentration 1 hour after the end of CPB (p less than 0.01). These observations demonstrate a release of endotoxin into the systemic circulation associated with tumor necrosis factor formation, which contributes to the whole-body inflammatory reaction associated with CPB.