IgA multiple myeloma is the second most frequent variant of multiple myeloma The median survival is about 3 years and depends on presence, or not, certain prognostic factors. Cytogenetic status has become the most important of them. The presence of the chromosome 13 deletion is an independent adverse prognostic marker in multiple myeloma and is associated with specific biological features. Patients with the chromosome 13 alterations are less likely to respond to treatment and have a shorter median overall survival. We present a case of IgA multiple myeloma, which was even resistant to new therapeutic strategies (thalidomide, bortezomib). less...

3'-Deuteriothalidomide was synthesized and found to be configurationally five times more stable than thalidomide toward racemization at physiological pH. less...

Mechanical damage to the spinal cord (SC) generates self-destructive processes that contribute to post-traumatic neurodegeneration. Because thalidomide apparently counteracts these effects its use clinically has been proposed enthusiastically. Nonetheless, we tested its action as a neuroprotectant in a clinically relevant model of SC injury in rats. We administered thalidomide intraperitoneally to rats subjected to thoracic SC contusion as single or repeated doses within the first 24 h after injury. Edema, neutrophil infiltration, and cord tissue preservation/destruction were assessed in the SC 24 h after injury and motor function for 7 weeks. Rats treated with thalidomide showed significant increase in SC water compared with naive rats, but not vehicle-treated rats; their neutrophil infiltration and amount of spared/destroyed cord tissue was not different from vehicle-treated rats; and in no case was motor performance improved after thalidomide. In conclusion, thalidomide failed here to be therapeutic, discouraging its use clinically for SC trauma. less...

ABSTRACT: BACKGROUND: Thalidomide based regimen is an effective and well tolerated therapy in multiple myeloma (MM) patients, however, there were a small number of studies written about the results of thalidomide therapy in non- transplant MM patients. We therefore conducted a retrospective study of 42 consecutive patients with newly diagnosed and relapsed/ refractory MM treated with thalidomide- based induction regimens followed by thalidomide maintenance therapy. RESULTS: Induction regimens with thalidomide and dexamethasone, and the oral combination of melphalan, prednisolone and thalidomide were administrated in 22 and 16 patients, respectively. The remaining 4 patients received other thalidomide- containing regimens. Twenty- nine patients received thalidomide as a salvage regimen. Twenty- three out of 26 patients achieving complete remission (CR) and very good partial remission (VGPR) received thalidomide maintenance. Of the 41 evaluable patients, median time of treatment was 21 months (3- 45 months), ORR was 92.7% with a 63.4% CR/VGPR. With a median follow up of 23 months, 3-year- PFS and 3-year-OS were 58.6 and 72.6%, respectively. Median time to progression was 42 months. While 3-year-PFS and 3-year-OS in non- transplant patients receiving thalidomide maintenance therapy were 67 and 80%, respectively. CONCLUSIONS: Prolonged thalidomide therapy enhanced survival rate and less frequently developed serious toxicity in non- transplant multiple myeloma patients. less...

A 67-year-old man was admitted to the hospital with symptoms of progressive dyspnoea. For 2 months he had received second-line treatment with dexamethasone and thalidomide for a multiple myeloma. Physical examination revealed a tachypnoeic patient and arterial blood gas analysis revealed a respiratory alkalosis and severe hypoxaemia. A high-resolution CT scan showed diffuse ground glass opacities in both lungs. Pulmonary function testing indicated severe diffusion capacity impairment. Bronchoalveolar lavage and cultures excluded the possibility of an infectious agent. The thalidomide treatment was discontinued whereupon the hypoxaemia and the ground glass opacities resolved and the diffusion capacity impairment improved. When a patient treated with thalidomide presents with dyspnoea and hypoxaemia with ground glass opacities, thalidomide-induced pneumonitis should be considered. Withdrawing thalidomide is the only treatment. less...

PURPOSE: Lenalidomide, a highly potent immunomodulatory derivative of thalidomide, potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells. A modular Phase I study of lenalidomide and paclitaxel in men with metastatic castration-resistant prostate cancer (CRPC) was conducted to assess PSA kinetics with lead-in lenalidomide and the feasibility of the combination. METHODS: Men with metastatic CRPC with prior taxane chemotherapy were planned for single-agent "lead-in" lenalidomide for 21/28 days at dose-levels: -1 (5 mg), 0 (10 mg), +1 (15 mg), +2 (20 mg), +3 (25 mg); followed by lenalidomide at the same dose and schedule in combination with weekly intravenous paclitaxel 100 mg/m(2) over 3 h on days 1, 8, 15 every 28 days utilizing a 3 + 3 dose-escalation design. RESULTS: Dose-limiting toxicity was observed in 4/6 patients with first-cycle combination therapy at the 10 mg dose-level and 3/6 patients at the 5 mg dose-level of lenalidomide, respectively. These included Grade 3 neutropenia precluding planned paclitaxel therapy (n = 3), grade 3 gastrointestinal toxicity (n = 2), chest pain (n = 1) and pulmonary embolism (n = 1). With lead-in lenalidomide, two patients with lymph-node dominant CRPC had a PSA-decline and regression in lymph node disease, respectively. Two of seven evaluable patients had PSA declines by 50% with combination therapy. Progression-free survival was 13 weeks (range 4-35 weeks). CONCLUSIONS: The high dose-limiting toxicity rates observed with lenalidomide and weekly paclitaxel require exploration of alternate dose-schedules of the combination in the second-line setting of CRPC. These early observations suggest distinctive toxicity and efficacy outcomes from thalidomide in combination with paclitaxel. less...

Background Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, Defibrotide showed activity in human myeloma xenografts DESIGN AND METHODS: Oral Melphalan was administered at 0.25 mg/kg, days 1-4, Prednisone at 1.5 mg/kg, days 1-4 and Thalidomide at 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4-4.8-7.2 g on days 1-4 and 1.6-3.2-4.8 g on days 5-35 RESULTS: Twenty-four relapsed/refractory myeloma patients were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%; the 1-year progression free survival and the 1-year overall survival were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in one patient only. Conclusions This combination showed anti-tumor activity with favourable tolerability. The maximum tolerated dose of Defibrotide was fixed at 7,2 g p.o. on day 1-4 followed by 4,8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs. less...

The use of nucleoside analog-based chemo-immunotherapeutic regimens over the last decade has significantly improved outcomes in patients with chronic lymphocytic leukemia (CLL). Nonetheless, virtually all patients with CLL relapse from chemoimmmunotherapy and current available therapies are not curative. Identifying therapies that effectively eliminate CLL cells and lack immunesuppression represent an exciting new therapeutic approach. IMiDs are a class of immunomodulating drugs that increase T-cell and NK-cell directed killing of tumor cells. The first generation molecule is thalidomide followed by a second generation molecule lenalidomide that lacks neurotoxicity and is being explored more extensively in clinical trials. Lenalidomide has been shown to benefit patients with multiple myeloma, myelodysplastic syndromes, and lymphoma. Initial reports in patients with relapsed and refractory CLL have shown promising responses. In a subset of patients with CLL complete responses have been noted. Subsequent studies, however, have suggested that this class of drug can also have serious and potentially life-threatening side effects including myelosuppression, tumor flare reaction and in a small subset of patients tumor lysis syndrome. Tumor flare with both thalidomide and lenalidomide appear to be disease specific to CLL and may reflect clinical manifestation of CLL tumor cell activation. As a consequence of these disease specific effects, the optimal safe dose of lenalidomide in CLL remains to be determined but appears to be lower than that tolerated in other B-cell malignancies. To date, biomarkers for response remain poorly defined and the relationship of clinical benefit to tumor flare is uncertain. This review examines the existing literature on the use of IMiDs in patients with CLL and provides suggestions for future research in this area. less...

Background: alpha-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. Patients and Methods: In a randomized phase II trial to assess tolerability and safety, we assigned patients with advanced slow-growing solid tumours to 1 of 6 two- or three-drug combinations: alpha-interferon 0.5 million IU b.i.d., thalidomide (100 mg b.i.d. reduced to 100 mg daily), or celecoxib (400 mg daily reduced to 200 mg). Circulating endothelial cells and progenitors (CECs, CEPs) and vascular endothelial growth factor were also studied. Results: From January 2002 to September 2005, 62 patients were enrolled. Four months after initiating treatment, 3 (4%) had partial response, 40 (64%) had stable disease and 19 (30%) had disease progression. Median duration of clinical benefit (partial response/stable disease) was 11.3 months. Patients receiving a third drug had significantly less stable disease plus partial response (chi(2) test, p = 0.002) than those receiving two drugs. The treatments were generally well tolerated, but neurotoxicity (G3 lethargy) occurred in 6 patients. Baseline CEPs were lower (p = 0.004) in patients with clinical benefit at 6 months than those without benefit. After 2 months of treatment CECs were lower than at baseline (p = 0.018) in patients without clinical benefit, and CEPs were higher than at baseline (p = 0.003) in patients with benefit. Conclusions: In pretreated patients with advanced slow-growing solid tumours, long-term metronomic administration of two-drug combinations of alpha-interferon, thalidomide or celecoxib was well tolerated and had antitumour activity. Low baseline CEPs in patients with subsequent clinical benefit suggest that CEC count may identify patients likely to benefit from long-term metronomic anti-angiogenic treatment. less...

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