Neonatal Hemostatic Disorders: Issues and Challenges.

Neonates form a unique cohort with distinct features associated with the hemostatic system compared with older children and adults. The development of the human hemostatic system begins around 10 weeks in utero and continues to evolve during childhood. This dynamic period termed developmental hemostasis should be taken into consideration when diagnosing a neonate with disorders of bleeding or thrombosis.

Targeting histone deacetylases (HDACs) and Wee1 for treating high-risk neuroblastoma.

BACKGROUND: Despite advances in treatment regimens, patients with high-risk neuroblastoma have long-term survival rates of < 40%. Wee1 inhibition in combination with CHK1 inhibition has shown promising results in neuroblastoma cells. In addition, it has been demonstrated that panobinostat can downregulate CHK1. Therefore, combination of panobinostat and MK-1775 may result in synergistic cytotoxicity against neuroblastoma cell lines. PROCEDURE: In vitro cytotoxicities of panobinostat and MK-1775 at clinically achievable concentrations, either alone or in combination, were evaluated in SK-N-AS, SK-N-DZ, and SK-N-BE(2) high-risk neuroblastoma cell lines using MTT assays. The mechanism of antitumor interaction was investigated using propidium iodide (PI) staining and flow cytometry analysis to determine apoptosis, as well as Western blotting to assess expression of phosphorylated CDK1/2, CHK1, and H2AX. RESULTS: Treatment of neuroblastoma cell lines with 500 nM MK-1775 caused growth arrest and apoptosis in SK-N-DZ and SK-N-AS, while it had minimal effect on the SK-N-BE(2) cell line. The combination of panobinostat and MK-1775 resulted in synergistic antitumor interactions in all three of the cell lines tested. MK-1775 treatment in SK-N-BE(2) cells induced increased levels of p-CHK1(S345) , which could be decreased by the addition of panobinostat. This was accompanied by increased DNA damage and apoptosis. CONCLUSIONS: The combination of panobinostat and MK-1775 has synergistic antitumor activity against neuroblastoma cell lines and holds promise as a potential treatment strategy for the management of high-risk neuroblastoma patients.

The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation.

Community respiratory viruses are significant causes of morbidity and mortality in patients with leukemia and hematopoietic stem cell transplant (HSCT) recipients. Data on characteristics and outcomes of parainfluenza virus (PIV) infections in these patients are limited. We reviewed the records of patients with leukemia and HSCT recipients who developed PIV infections to determine the characteristics and outcomes of such infections. We identified 200 patients with PIV infections, including 80 (40%) patients with leukemia and 120 (60%) recipients of HSCT. At presentation, most patients (70%) had an upper respiratory tract infection and the remaining patients (30%) had pneumonia. Neutropenia, APACHE II score more than 15, and respiratory coinfections were independent predictors of progression to pneumonia on multivariate analysis. Overall mortality rate was 9% at 30 days after diagnosis and 17% among patients who had PIV pneumonia, with no significant difference between patients with leukemia and HSCT recipients (16% vs 17%). On multivariate analysis, independent predictors of death were relapsed or refractory underlying malignancy, APACHE II score more than 15, and high-dose steroid use. Patients with leukemia and HSCT are at risk for serious PIV infections, including PIV pneumonia, with a significant mortality rate. We identified multiple risk factors for progression to pneumonia and death.

Tigecycline use in cancer patients with serious infections: a report on 110 cases from a single institution.

Tigecycline, the first in a new class of glycylcyclines, has been approved for the treatment of complicated skin and skin structure and intraabdominal infections in adults. However, clinical data on its safety and effectiveness in cancer patients are lacking. We reviewed the records of all cancer patients treated with tigecycline for more than 48 hours between June 2005 and September 2006 at our institution and identified 110 consecutive cases (median age, 58 yr; range, 18-81 yr). We collected data on demographics, cancer type, tigecycline indication, microbiologic characteristics, side effects, and outcome. Sixty-four (58%) patients had hematologic malignancies; 27 patients had undergone hematopoietic stem cell transplantation. Thirty-one (28%) patients had neutropenia, and 62 (56%) were in the intensive care unit at the start of therapy. Most patients (106 [96%]) received tigecycline as a second-line agent (after not responding to other broad-spectrum antibiotics), and 101 (92%) received it in combination with an antipseudomonal drug. The mean duration of therapy was 11 days (range, 3-35 d). Sixty-six (60%) patients received tigecycline for refractory pneumonia, 19 (17%) had bacteremia, 9 (8%) had intraabdominal infections, and 7 (6%) had complicated skin and soft tissue infections. Fifty (45%) patients had microbiologically documented infections, and the remaining patients had negative cultures at the start of therapy.An overall clinical response was noted in 70 (64%) patients. More clinical responses were seen in patients with bacteremia than in those with pneumonia (79% vs. 51%; p = 0.029). Patients with microbiologically documented infections had significantly higher clinical response rates than patients with non-microbiologically documented infections (73% vs. 55%; p = 0.047). Forty (36%) patients did not respond to treatment; 36 of these patients died of active infection during tigecycline therapy. Patients with pneumonia had a significantly higher mortality rate than patients with bacteremia (44% vs. 16%; p = 0.026). During the 60 days of follow-up from the date of clinical response, patients with pneumonia had significantly shorter survival durations than patients with other infections. Of the 42 patients who were not on antiemetics or ventilator support at the start of tigecycline therapy, 2 (5%) experienced mild nausea, and 1 (2%) experienced nausea and vomiting. Only 4 (4%) patients overall experienced diarrhea during tigecycline therapy, all of whose stools were negative for Clostridium difficile toxin. No serious adverse events related to tigecycline use were identified. The combination of tigecycline and an antipseudomonal drug may be appropriate for treating refractory infections and multidrug-resistant organisms in cancer patients, including hematopoietic stem cell transplant recipients. Patients with refractory pneumonia had a relatively low clinical response rate in our study.