Efficacy of Dasatinib in a CML Patient in Blast Crisis with F317L Mutation: A Case Report and Literature Review.

The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has significantly increased survival rate and quality of life for patients with CML. Despite the high efficacy of imatinib, not all patients benefit from this treatment. Resistance to imatinib can develop from a number of mechanisms. One of the main reasons for treatment failure is a mutation in the BCR-ABL gene, which leads to therapy resistance and clonal evolution. Clearly, new treatment approaches are required for patients who are resistant to imatinib. However, mutated clones are usually susceptible to second-generation TKIs, such as nilotinib and dasatinib. The choice of the therapy depends on the type of mutation. A large trial program showed that dasatinib is effective in patients previously exposed to imatinib. However, for a minority of patients who experience treatment failure with TKI or progress to advanced-phase disease, allogeneic stem cell transplantation (allo-SCT) remains the therapeutic option. In spite of the high curative potential of allo-SCT, its high relapse rate still requires a feasible strategy of posttransplant treatment and prophylaxis. We report a case of a CML patient with primary resistance to first-line TKI therapy. The patient developed an undifferentiated blast crisis. Before dasatinib therapy, the patient was found to have an F317L mutation. He was successfully treated with dasatinib followed by allo-SCT. In the posttransplant period, preemptive dasatinib treatment was used to prevent disease relapse.

Declines in highly active antiretroviral therapy initiation at CD4 cell counts ≤ 200 cells/µL and the contribution of diagnosis of HIV at CD4 cell counts ≤ 200 cells/µL in British Columbia, Canada.

OBJECTIVES: The aim of the study was to examine trends in initiating highly active antiretroviral therapy (HAART) with a CD4 count ≤ 200 cells/µL and the contribution of having a CD4 count ≤ 200 cells/µL at the time of diagnosis to these trends, in British Columbia (BC), Canada. METHODS: We included in the analysis treatment-naïve BC residents aged ≥ 19 years who initiated HAART from 2003 to 2012. Participants were classified as follows: Group 1: diagnosed and initiated HAART with a CD4 count > 200 cells/µL; Group 2: diagnosed with a CD4 count > 200 cells/µL and initiated HAART with a CD4 count ≤ 200 cells/µL; and Group 3: diagnosed and initiated HAART with a CD4 count ≤ 200 cells/µL. We measured trends in initiating HAART with a CD4 count ≤ 200 cells/µL and used logistic regression models to measure factors associated with initiating HAART with a CD4 count ≤ 200 cells/µL, stratified by having a CD4 count ≤ 200 cells/µL or > 200 cells/µL at the time of diagnosis. RESULTS: Between 2003 and 2012, 3506 BC residents initiated HAART. Of these, 44% (1558 of 3506) initiated HAART with a CD4 count ≤ 200 cells/µL. This proportion declined from 69% (198 of 287) in 2003 to 21% (81 of 330) in 2012 (P < 0.001). The proportion of those in Group 3 increased from 49% (97 of 198) in 2003 to 69% (56 of 81) in 2012 (P < 0.001). Overall, 56% (1948), 22% (776) and 22% (782) made up Groups 1, 2, and 3, respectively. In adjusted analyses, seeing a specialist was significantly associated with being in Group 3. Using injection drugs and seeing a specialist were associated with being in Group 2. CONCLUSIONS: In recent years, among individuals who ever initiated HAART in BC, being diagnosed with low CD4 cell counts has become a greater contributor to initiating HAART with low CD4 cell counts.

Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells.

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.