Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia

Treatment of advanced-phase chronic myeloid leukemia (CML) remains unsatisfactory. Single-agent tyrosine kinase inhibitors have modest and short-lived activity in this setting. We conducted a phase I/II study to determine safety and efficacy of the combination of dasatinib and decitabine in patients with advanced CML. Two different dose schedules were investigated with a starting decitabine dose of either 10 mg/m² or 20 mg/m² daily for 10 days plus dasatinib 100 mg daily. The target dose level was decitabine 10 mg/m² or 20 mg/m² daily for 10 days plus dasatinib 140 mg daily. Thirty patients were enrolled, including seven with accelerated-phase CML, 19 with blast-phase CML, and four with Philadelphia-chromosome positive acute myeloid leukemia. No dose-limiting toxicity was observed at the starting dose level with either schedule. Grade ≥3 treatment emergent hematological adverse events were reported in 28 patients. Thirteen patients (48%) achieved a major hematologic response and six (22%) achieved a minor hematologic response, with 44% of these patients achieving a major cytogenetic response and 33% achieving a major molecular response. Median overall survival (OS) was 13.8 months, with significantly higher OS among patients who achieved a hematologic response compared to non-responders (not reached vs 4.65 months; P < .001). Decitabine plus dasatinib is a safe and active regimen in advanced CML. Further studies using this combination are warranted.     

The clinical impact of time to response in de novo accelerated-phase chronic myeloid leukemia

We aimed to describe the impact of time to response on the outcomes of 75 patients with accelerated-phase chronic myeloid leukemia (CML-AP) at diagnosis. Patients had at least 1 feature of AP: blasts ≥15% (n = 2), basophils ≥20% (n = 19), platelets <100 × 10⁹/L (n = 7), cytogenetic clonal evolution (n = 34), or more than one factor (n = 13). Thirty-three patients received imatinib; 42 received a second-generation tyrosine kinase inhibitor (2GTKI) (19 dasatinib and 23 nilotinib). We used chi-square and Kaplan-Meier analyses to determine the impact of various degrees of molecular and cytogenetic response at early time points (3 and 6 months) on rates of overall cytogenetic and molecular response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). After a median follow-up of 96 months (range: 18-224 months), the overall rate of complete cytogenetic response was 79%, of major molecular response, 71%, and of molecular reponse (MR)4.5, 59%. Patients who achieved a major cytogenetic response (MCyR) (n = 49) at 3 months had significantly better 3-year OS (94% vs 75%; P = .002), TFS (98% vs 73%; P < .001), EFS (93% vs 42%; P < .001), and FFS (83% vs 25%; P < .001) rates than patients who did not have MCyR at 3 months. Most (67%) who eventually achieved sustained MR4.5 had achieved MCyR at 3 months. In de novo CML-AP, early response at 3 and 6 months is a strong determinant of long-term outcome.     

Investigating a crow die-off in January–February 2011 during the introduction of a new clade of highly pathogenic avian influenza virus H5N1 into Bangladesh

We investigated unusual crow mortality in Bangladesh during January-February 2011 at two sites. Crows of two species, Corvus splendens and C. macrorhynchos, were found sick and dead during the outbreaks. In selected crow roosts, morbidity was ~1 % and mortality was ~4 % during the investigation. Highly pathogenic avian influenza virus H5N1 clade 2.3.2.1 was isolated from dead crows. All isolates were closely related to A/duck/India/02CA10/2011 (H5N1) with 99.8 % and A/crow/Bangladesh/11rs1984-15/2011 (H5N1) virus with 99 % nucleotide sequence identity in their HA genes. The phylogenetic cluster of Bangladesh viruses suggested a common ancestor with viruses found in poultry from India, Myanmar and Nepal. Histopathological changes and immunohistochemistry staining in brain, pancreas, liver, heart, kidney, bursa of Fabricius, rectum, and cloaca were consistent with influenza virus infection. Through our limited investigation in domesticated birds near the crow roosts, we did not identify any samples that tested positive for influenza virus A/H5N1. However, environmental samples collected from live-bird markets near an outbreak site during the month of the outbreaks tested very weakly positive for influenza virus A/H5N1 in clade 2.3.2.1-specific rRT-PCR. Continuation of surveillance in wild and domestic birds may identify evolution of new avian influenza virus and associated public-health risks.     

Immunomodulatory and antimicrobial non-mulberry Antheraea mylitta silk fibroin accelerates in vitro fibroblast repair and regeneration by protecting oxidative stress

The antimicrobial nature of Antharaea mylitta silk-fibroin (SF) is reported but antioxidant potential and the immunomodulatory role towards the fibroblast cell repair process is not explored. Polyurethane is reported to have inflammatory potential by mononuclear cells directed cytokine release, which can guide fibroblast repair. Present study demonstrates the conjunctive effect of inflammatory PU/SF to regulate the favorable shift from pro-inflammatory to anti-inflammatory cytokine stimulation for accelerated fibroblast repair. Minimal inhibitory concentration of SF was determined against pathogenic strains and the effect of SF was investigated for fibroblast NIH3T3 cell adhesion. SF doses (8, 8.5, 9 mg mL⁻¹) were found to be greater than both the IC₅₀ of DPPH scavenging and the ED₅₀ for NIH3T3 proliferation. Anti-lipid peroxidase (ALP) activity of SF doses and citric acid-treated NIH3T3 cells were compared under hydrogen peroxide (H₂O₂) induced oxidative stress. 9 mg mL⁻¹ SF showed greater ALP activity than the citric acid standard. SF-driven protection to oxidative damage was measured by viable cell fraction in trypan blue dye exclusion assay where 9 mg mL⁻¹ SF showed the highest viability (p ≤ 0.05). 9 mg mL⁻¹ SF was blended with PU for scaffold (w/v = 2 : 5, 2 : 7, 2 : 9) fabrication. The protective effect of PU/SF (2 : 5, 2 : 7, 2 : 9) against oxidative stress was verified by damaged cell survival in MTT assay and DNA quantification. The highest number of cells survived on PU/SF (2 : 9) at all intervals (p ≤ 0.01) upon oxidative damage; PU/SF (2 : 9) was also fabricated by employing the immobilization technique. Immobilized PU/SF (2 : 9) exhibited a greater zone of microbial inhibition, a higher extent of inhibition to microbial adherence, and caused more LDH release from bacterial cell membrane due to membrane rupture, resulting in bacterial cell death (E. coli, K. pneumoniae, P. aeruginosa, S. aureus) compared to the experimental results shown by blended PU/SF (2 : 9). The protective nature of PU/SF (2 : 9) against oxidative stress was ensured through the LDH activity of damaged NIH3T3 cells. Initial raised IL-6, TNF-alpha (pro-inflammatory cytokines) and lowered IL-8, IL-10 (anti-inflammatory cytokine) profiles coupled with fallen IL-6, TNF-alpha, and elevated IL-8, IL-10 at later hours synergistically progress the inflammatory phase of in vitro scratch wound repair in mononuclear culture treated by PU/SF (2 : 9).

Initially SF accelerated pro-inflammatory cytokines, restricted anti-inflammatory cytokines; later it regulated in reverse order. SF potentially eradicated ROS and promoted Ki-67 cellular regeneration whereas pristine PU could not.     

Repetitive Transcranial Magnetic Stimulation for Generalized Anxiety Disorder: A Systematic Literature Review and Meta-Analysis

BackgroundAnxiety disorders such as generalized anxiety disorder (GAD) impact 10% of the US population, and many patients do not completely respond to first-line treatments (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and psychotherapy). Given the dearth of evidence for non-pharmacologic, non-psychotherapeutic interventions, we performed a systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) in adults with GAD.MethodsA systematic literature review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was conducted. Pre- and post-treatment anxiety scores were extracted, and a random-effects meta-analysis was conducted to determine the magnitude of improvement (standardized mean difference). Standard assessments of heterogeneity (e.g., Q-statistic, I², and τ ²) and publication bias were performed.ResultsThe initial search resulted in 3194 citations, of which 6 studies were included in the meta-analysis. In total, 152 patients were studied, including 97 patients who received active treatment and 55 who received sham treatment, and heterogeneity was modest (I² 13.32, Q = 5.77). In patients with GAD, rTMS produced a standardized mean difference of −1.857 (confidence interval: −2.219 to −1.494; P < .001) with a prediction interval of −2.55 to −1.16.ConclusionsThe results suggest a robust effect of rTMS in GAD in the context of limited, heterogenous studies. Rigorously designed, randomized controlled trials of rTMS for GAD and related anxiety disorders are urgently needed. These studies will provide opportunities for biomarker development and integration of concurrent evidence-based psychotherapy to maximize results.     

Developments in the Field of Myeloma in the Last Decade

The plasma cell disorders constitute a heterogeneous group of diseases. Accumulation of knowledge in the field has helped us to understand these diseases better, stage them more precisely, prognosticate more accurately and manage them more effectively. The paradigm shift in the management of multiple myeloma over the last one-and-a-half decades shows no signs of slackening. In addition to novel therapies, better supportive care and high-dose melphalan with autologous hematopoietic stem cells have contributed to this positive outcome. This review summarizes the developments in this sphere in the recent past.