Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

BACKGROUND: Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. METHODS: In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. FINDINGS: Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. INTERPRETATION: Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

Multicolor interphase cytogenetics for the study of plasma cell dyscrasias.

Specific chromosomal abnormalities such as chromosome 13 deletions and some translocations affecting the immunoglobulin heavy chain (IGH) gene, namely t(4;14)(p16;q32) and t(14;16)(q32;q23) have been associated with an adverse prognosis in multiple myeloma. Conventional cytogenetic techniques fail to detect these aberrations in the majority of cases. Thus, we have developed a novel set of interphase fluorescence in situ hybridization (I-FISH) assays targeting those regions frequently lost on chromosome 13 as well as those oncogenes most recurrently involved in translocations with the IGH locus in multiple myeloma, i.e. IRTA1/2 (1q21), FGFR3/MMSET (4p16), CCND3 (6p21), IRF4 (6p25), CCND1 (11q13), MAF (16q23), and MAFB (20q12). The probes were combined in a multicolor fashion to develop novel multicolor I-FISH (MI-FISH) assays, whose validity and applicability was evaluated in negative controls and in a series of 13 plasma cell neoplasias. Additionally, a combination of the novel MI-FISH assays with staining for the plasma cell-specific antigen VS38c by means of multicolor FICTION (M-FICTION, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms) allowed us to selectively analyze the plasma cell compartment, and thereby to increase the assay sensitivity.

Pain in oxaliplatin-induced neuropathy--sensitisation in the peripheral and central nociceptive system.

BACKGROUND: This study aimed to determine the somatosensory characteristics and pain types in patients with acute oxaliplatin-induced neuropathy and to relate this profile to the hereby detected underlying pathophysiological mechanisms. PATIENTS AND METHODS: Sixteen patients treated with oxaliplatin for cancer were characterised with neurological assessment and a standardised and validated set for quantitative sensory testing (QST). Patients were allocated to two groups depending on the presence or absence of pain symptoms of acute neuropathy. RESULTS: Comparison with normative data revealed in patients with pain symptoms a characteristic somatosensory profile of cold and mechanical hyperalgesia. Group-to-group analysis revealed additional heat hyperalgesia and warm hypoesthesia. CONCLUSION: Pain symptoms of acute oxaliplatin-induced neuropathy are related to signs of sensitisation within the peripheral (cold and heat hyperalgesia) and central nervous nociceptive system (mechanical hyperalgesia). This strengthens the rationale for treatment with anticonvulsants and antidepressants and fosters research on ion channel and receptor related mechanisms.

Establishment and optimization of a flow cytometric method for evaluation of viability of CD34+ cells after cryopreservation and comparison with trypan blue exclusion staining.

BACKGROUND: Trypan blue exclusion staining is probably the most frequently applied method (Method I) for assessment of viability in peripheral blood progenitor cell grafts after cryopreservation. Alternatively, a flow cytometry-based method (Method II) was established and optimized. STUDY DESIGN AND METHODS: In a first series of 22 autologous apheresis products, the influence of duration of antibody staining and red cell (RBC) lysis on viability was investigated. In a second series of 21 autologous and 1 allogeneic apheresis products, the effect of omitting the RBC lysis was evaluated. On the basis of the results of the first two series, 155 autologous and 57 allogeneic apheresis products were analyzed with Method I and the now optimized Method II. RESULTS: Halving the incubation times did not influence the viability of CD45+ or CD34+ cells. Omission of RBC lysis resulted in a significantly (p = 0.022) increased median viability of CD45+ cells (75.8% vs. 71.0%) without any influence on CD34+ cells. In the third series, the median viability of CD34+ cells (96.9%) was significantly (p < 0.0001) higher compared with the viability of CD45+ cells (76.2%) and the viability determined by Method I (86.5%). CONCLUSION: The viability of CD34+ cells was significantly higher compared with the viability of all white blood cells. The presented cytometry-based method is superior to the standard trypan blue method regarding the number of analyzable cells and documentation, regarding observer independence and standardization; it allows the analysis of the cells of interest for transplantation after minimal sample manipulation.

TITANOTHERE ALLOMETRY, HETEROCHRONY, AND BIOMECHANICS: REVISING AN EVOLUTIONARY CLASSIC.

A reanalysis of Osborn's titanothere data indicates that extrapolative growth of a constant allometric relationship alone ("hypermorphosis") does not account for the trend toward body and horn size increase. Empirically, we also observe possible positive changes in the y-intercept ("predisplacement" or early onset of development), and possibly, changes in the slope ("acceleration/neoteny" or changes in growth rate) between the Oligocene and Eocene groups. Theoretically, these may be responses to more massive body shapes, perforce accompanying size increase, which increase the amount of force to which the horns were subjected.