Citations

Abstract In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Purpose To assess the impact of age on outcome and to analyze the projected years of life lost in patients with multiple myeloma. Patients and Methods Ten thousand five hundred forty-nine patients were evaluated; 6,996 patients were treated with conventional chemotherapy, and 3,553 patients were treated with high-dose therapy with autologous stem-cell transplantation. Results Mean observed and relative overall survival times in the entire cohort were 3.7 and 3.9 years, respectively. Observed survival decreased steadily from 6.4 years in patients younger than age 50 years to 2.5 years in patients ≥ age 80 years. A similar decrease was noted for relative survival. Higher age correlated significantly with higher International Staging System (ISS) stage. Relative excess risk of death differed significantly between 10-year age cohorts beginning from age 40 years (P < .001 for age 50 to 59 v age 40 to 49, P < .001 for age 60 to 69 v age 50 to 59, P < .001 for age 70 to 79 v age 60 to 69, and P = .009 for age ≥ 80 v 70 to 79). The average years of life lost per patient was 16.8 years in the entire patient cohort and decreased steadily from 36.1 years in patients younger than 40 years old to 4.6 years in patients ≥ age 80 years. Conclusion Age is associated with higher ISS stage and is an important risk factor for early mortality. Survival declined continuously by each decade from age 50 to age ≥ 80 from more than 6 to less than 3 years. The average of years of life lost in patients with myeloma is higher than in many other cancers and amounts to more than 30 years in patients younger than 40 years old but decreases to less than 5 years in patients age 80 years or older.

Objective:To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit.Methods:An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment.Results:A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. Conclusions: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available. Multiple Sclerosis (2002)8,19-23

AbstractWe analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P < .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

CD38 controls the chemotaxis of leukocytes to some, but not all, chemokines, suggesting that chemokine receptor signaling in leukocytes is more diverse than previously appreciated. To determine the basis for this signaling heterogeneity, we examined the chemokine receptors that signal in a CD38-dependent manner and identified a novel “alternative” chemokine receptor signaling pathway. Similar to the “classical” signaling pathway, the alternative chemokine receptor pathway is activated by Gαi2-containing Gi proteins. However, unlike the classical pathway, the alternative pathway is also dependent on the Gq class of G proteins. We show that Gαq-deficient neutrophils and dendritic cells (DCs) make defective calcium and chemotactic responses upon stimulation with N-formyl methionyl leucyl phenylalanine and CC chemokine ligand (CCL) 3 (neutrophils), or upon stimulation with CCL2, CCL19, CCL21, and CXC chemokine ligand (CXCL) 12 (DCs). In contrast, Gαq-deficient T cell responses to CXCL12 and CCL19 remain intact. Thus, the alternative chemokine receptor pathway controls the migration of only a subset of cells. Regardless, the novel alternative chemokine receptor signaling pathway appears to be critically important for the initiation of inflammatory responses, as Gαq is required for the migration of DCs from the skin to draining lymph nodes after fluorescein isothiocyanate sensitization and the emigration of monocytes from the bone marrow into inflamed skin after contact sensitization.

AbstractThe AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)