This is the first report giving evidence that SAHA and bortezomib synergistically induce apoptosis in MCL cells. These data build the framework for clinical trials using combined proteasome and histone deacetylase inhibition in the treatment of MCL.
The purpose of the present study was to evaluate the incidence, spectrum and extent of psychiatric symptoms in patients with malignant melanoma (MM) before and during adjuvant treatment with interferon-alpha (IFN-alpha). 850 patients with cutaneous MM of > or =1.5 mm tumor thickness received standard low-dose IFN-alpha 2a in this prospective multicenter trial of the Dermatologic Cooperative Oncology Group (DeCOG). Psychiatric symptoms were evaluated at baseline and after 3, 6, and 12 months with the Beck Depression Inventory (BDI) and the Symptom Check List 90-Revised (SCL 90-R). In all, 282 patients completed all questionnaires. Mean BDI depression scores increased significantly during the first 6 months of IFN-alpha treatment (P < or =0.001), followed by a mild but not significant decrease. Also mean SCL 90-R scores increased significantly during the first 3 months of adjuvant treatment with IFN-alpha (P< or =0.001) and remained elevated until month 12 (P< or =0.001). Only 5% developed BDI scores >10, indicating a clinically significant depressive syndrome and only 1.4% reached a BDI score > or =18, indicating a moderate to severe depressive syndrome. Patients, who dropped-out early from psychiatric reasons, had significantly increased BDI and SCL-90R scores at baseline. Women scored higher in both scales before and during treatment if compared with men. In conclusion, adjuvant treatment with IFN-alpha was associated with a significant increase of BDI- and SCL 90-R scores. A higher pretreatment depression score was found to be a risk factor for an early drop-out during therapy. Pretreatment screening and an interdisciplinary care of the patients is recommended.
Multiple myeloma (MM) is a malignancy with excessive production of monoclonal proteins. At disease presentation 30% of MM patients have significant renal impairment which may progress to renal failure requiring dialysis. Besides chemotherapy extracorporeal elimination procedures such as plasma exchange have been applied as adjuvant strategies to eliminate free light chains from circulating blood, however the efficacy was poor with older techniques. We report about a highly efficient method to eliminate serum free light chain (sFLC) using a newly designed protein leaking membrane in patients suffering from sFLC induced acute renal failure. The protein leaking membrane (HCO 1100) is characterized by increased pore size facilitating elimination of middle molecules such as sFLC kappa (22.5 kD). The HCO 1100 membrane was applied in a hemodialysis and hemodiafiltration mode and compared to standard procedures (high flux hemodialysis, hemodiafiltration and plasma exchange). Hemodiafiltration with the protein leaking membrane HCO 1100 was superior to all other extracorporeal replacement strategies in eliminating sFLC-kappa from circulating blood. A median blood reduction rate of 40.8% (range 13.9% - 66.4%) was achieved during hemodiafiltration. The corresponding peak clearance rate was 25 ml/min. Importantly, the poorest elimination rate was achieved by plasma exchange followed by standard high flux hemodialysis. Extracorporeal elimination strategies with the protein leaking membrane HCO 1100 may be a promising adjuvant treatment strategy for patients with sFLC nephropathy requiring dialysis. Hemodiafiltration and to lesser extend also hemodialysis with the HCO 1100 hemofilter are able to eliminate substantial amounts of sFLC kappa in MM patients.
Prognostic markers are important to identify high-risk patients in Multiple Myeloma (MM). Several prognostic models have been published, including parameters of tumor burden and cytogenetics. Recently the International Staging System (ISS) for Multiple Myeloma, which includes beta2-microglobulin (beta2-MG) and albumin, has been introduced for newly diagnosed patients with symptomatic MM. We previously reported about the prognostic significance of circulating proteasome levels (cProteasomes) in MM patients (Jakob et al., Blood 2007). In the present study we investigated the prognostic relevance of the bone resorption marker carboxy-terminal telopeptide of type-I collagen (ICTP) and cProteasome levels in comparison to the classical prognostic factors (beta2-MG), albumin, deletion 13q14 and type of chemotherapy (high-dose-therapy versus conventional dose chemotherapy) in 92 patients with newly diagnosed active MM. ICTP and cProteasome were significantly elevated parallel to ISS stages (P<0.001). ICTP (cut off: normal value), cProteasome levels (cut off: median value) and a combined ICTP-cProteasome score (1: ICTP < normal value and cProteasome < median; 2: one of both parameters elevated; 3: both parameters elevated) were significant univariate prognostic factors for overall survival in active MM (P<0.001, P=0.002 and P<0.001, respectively). Survival rates at 5-yrs were 95%, 66% and 27% in the groups of patients with ICTP-cProteasome score 1, 2 and 3, respectively. In a further analysis ICTP alone and the combined ICTP-cProteasome score significantly separated each of the three ISS stages into two distinct groups with a better versus worse prognosis. In a multivariate Cox regression analysis, including beta2-MG, albumin, deletion 13q14, type of chemotherapy, cProteasome levels and ICTP, ICTP was the parameter with the strongest prognostic power (P<0.001, hazard-ratio: 7.9) and cProteasomes (P=0.011, hazard-ratio: 3). Our study underlines that the activity of myeloma bone disease, as reflected by the collagen-I degradation product ICTP, has a major impact on the prognosis of symptomatic MM. This result is in line with published data showing a positive feedback between myeloma cells and osteoclasts, i.e. a vicious cycle. The inclusion of the bone resorption marker ICTP and cProteasome levels into multivariate models add substantial prognostic information on overall survival in newly diagnosed active MM.
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