Roland Chu

Short-Dwell Ethanol Lock Therapy in Children Is Associated With Increased Clearance of Central Line–Associated Bloodstream Infections

Background. Central line–associated bloodstream infection (CLABSI) is a known complication of central line use. Salvage of infected central lines with ethanol lock therapy (ELT) with systemic antimicrobials may be an alternative treatment option in children. Methods. Retrospective review was performed in children with CLASBI who underwent short-dwell ELT (70% ethanol, 4- to 25-hour dwell times ≤3 days) with systemic antimicrobials from January 1, 2007 to July 15, 2009. Results. A total of 59 patients, aged 2 months to 19 years (mean ± SD = 6.3 ± 6.1 years) with 80 episodes of CLABSI were included. The CLABSI eradication rate was 86% (69/80 episodes; 95% confidence interval [CI] 78%, 94%), significantly greater than 50% (Z = 2.35, P < .05), the estimated clearance rate of CLABSI eradication using systemic antimicrobials alone. Overall central line retention was 78% (60/77 episodes, 95% CI 69%, 87%). ELT was well tolerated. Conclusions. These findings suggest the potential benefit of short-dwell ELT combined with systemic antimicrobials in CLABSI treatment. Randomized controlled trials are needed.

Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML cells

Purpose: To investigate the molecular mechanism underlying intrinsic resistance to ABT-199. Experimental Design: Western blots and real-time RT-PCR were used to determine levels of Mcl-1 after ABT-199 treatment alone or in combination with cytarabine or daunorubicin. Immunoprecipitation of Bim and Mcl-1 were used to determine the effect of ABT-199 treatment on their interactions with Bcl-2 family members. Lentiviral short hairpin RNA knockdown of Bim and CRISPR knockdown of Mcl-1 were used to confirm their role in resistance to ABT-199. JC-1 assays and flow cytometry were used to determine drug-induced apoptosis. Results: Immunoprecipitation of Bim from ABT-199–treated cell lines and a primary patient sample demonstrated decreased association with Bcl-2, but increased association with Mcl-1 without corresponding change in mitochondrial outer membrane potential. ABT-199 treatment resulted in increased levels of Mcl-1 protein, unchanged or decreased Mcl-1 transcript levels, and increased Mcl-1 protein half-life, suggesting that the association with Bim plays a role in stabilizing Mcl-1 protein. Combining conventional chemotherapeutic agent cytarabine or daunorubicin with ABT-199 resulted in increased DNA damage along with decreased Mcl-1 protein levels, compared with ABT-199 alone, and synergistic induction of cell death in both AML cell lines and primary patient samples obtained from AML patients at diagnosis. Conclusions: Our results demonstrate that sequestration of Bim by Mcl-1 is a mechanism of intrinsic ABT-199 resistance and supports the clinical development of ABT-199 in combination with cytarabine or daunorubicin for the treatment of AML. Clin Cancer Res; 22(17); 4440–51. ©2016 AACR.

Who Treats Adolescents and Young Adults with Cancer? A Report from the AYA HOPE Study

PURPOSE Physicians play a critical role in delivering effective treatment and enabling successful transition to survivorship among adolescent and young adult (AYA) cancer patients. However, with no AYA cancer medical specialty, information on where and by whom AYAs with cancer are treated is limited. METHODS Using the National Cancer Institutes population-based AYA HOPE Study, 464 AYAs aged 15-39 at diagnosis treated by 903 physicians were identified. Differences in physician and hospital characteristics were examined by age at diagnosis and cancer type (germ cell cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, acute lymphocytic leukemia [ALL], and sarcoma) using chi-square tests. RESULTS Treating physicians were predominately 51-64 years old, male, United States-trained in non-pediatric specialties, and in group practices within large metropolitan areas. Older patients were less often treated by pediatric physicians (p < 0.01) and more likely to be treated by United States-trained physicians without research/teaching responsibilities and in hospitals without residency programs (p < 0.05). The majority of the few pediatricians (n = 44) treated ALL patients. Physicians with research/teaching responsibilities and those based in medical schools were more likely to treat patients with ALL and sarcoma compared with other cancer types (p < 0.01). Of HL patients, 73% were treated at a cancer center compared with 56% of patients with germ cell cancer (p < 0.01), while ALL (85%) and sarcoma (87%) patients were more likely to be treated in hospitals with residency programs (p < 0.01). CONCLUSIONS Most AYAs with cancer were treated by non-pediatric physicians in community settings, although physician characteristics varied significantly by patient cancer type and age at diagnosis.

Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775- and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

Mechanisms responsible for the synergistic antileukemic interactions between ATR inhibition and cytarabine in acute myeloid leukemia cells

Acute myeloid leukemia (AML) continues to be a challenging disease to treat, thus new treatment strategies are needed. In this study, we investigated the antileukemic effects of ATR inhibition alone or combined with cytarabine in AML cells. Treatment with the ATR-selective inhibitor AZ20 caused proliferation inhibition in AML cell lines and primary patient samples. It partially abolished the G2 cell cycle checkpoint and caused DNA replication stress and damage, accompanied by CDK1-independent apoptosis and downregulation of RRM1 and RRM2. AZ20 synergistically enhanced cytarabine-induced proliferation inhibition and apoptosis, abolished cytarabine-induced S and G2/M cell cycle arrest, and cooperated with cytarabine in inducing DNA replication stress and damage in AML cell lines. These key findings were confirmed with another ATR-selective inhibitor AZD6738. Therefore, the cooperative induction of DNA replication stress and damage by ATR inhibition and cytarabine, and the ability of ATR inhibition to abrogate the G2 cell cycle checkpoint both contributed to the synergistic induction of apoptosis and proliferation inhibition in AML cell lines. Synergistic antileukemic interactions between AZ20 and cytarabine were confirmed in primary AML patient samples. Our findings provide insight into the mechanism of action underlying the synergistic antileukemic activity of ATR inhibition in combination with cytarabine in AML.

The Impact of Ethanol Lock Therapy on Length of Stay and Catheter Salvage in Pediatric Catheter-Associated Bloodstream Infection

Background. Ethanol lock therapy (ELT) with systemic antimicrobial therapy (SAT) is a treatment for catheter-associated bloodstream infections (CABSI). However, its impact on hospital length of stay (LOS) is unknown. Objectives. Assess the impact of ELT on LOS, LOS attributable to CABSI (ALOS), and catheter salvage in pediatric hematology, oncology, stem cell transplant (HOSCT) CABSI. Methods. Retrospective review of HOSCT CABSI from January 2009 to July 2011. Results. A total of 124 CABSI episodes were reviewed in 66 patients. Mean LOS with ELT after 1 positive blood culture (BC) was 7.1 versus 12.3 days after ≥2 positive BC (P = .014). Mean ALOS was 1.6 days with ELT versus 2.9 days without ELT (P = .018). Mean ALOS with ELT after 1 positive BC was 3.75 days versus 5.8 days after ≥2 positive BC (P = .022). Catheter salvage rate: 41 of 48 (85%) with ELT versus 49 of 68 (72%) without ELT (P = .169). Conclusion. Earlier initiation of ELT may decrease ALOS.

A multidisciplinary approach to determine heparin dosing in pediatric vascular devices.

In the health care community, nurses are important agents of change and vehicles for improvements in clinical practice and policy. Pediatric nurses empowered with the tools of evidence-based practice and clinical expertise collaborated in 2007 with other health care professionals to make changes in clinical practice for pediatric patients with vascular access devices (VADs). Nurses recognized that there was a need for a change in the heparinization policy for children with short- and long-term VADs. Data were methodically collected over a 1-year period on 500 VAD. Data collection demonstrated a range of VAD volumes that did not exceed 2 mL. The group analysis of the results gave support for changes in the volumes needed for heparinization. Establishment of appropriate heparin dosing based on scientific data led to a decrease in heparin used to maintain pediatric VAD patency and aided in lowering the risk of side effects in patients.

Gene Signature of High White Blood Cell Count in B-Precursor Acute Lymphoblastic Leukemia

In this study we sought to identify genetic factors associated with the presenting white blood cell (WBC) count in B-precursor acute lymphoblastic leukemia (BP-ALL). Using ETV6-RUNX1-positive BP-ALL patient samples, a homogeneous subtype, we identified 16 differentially expressed genes based on the presenting WBC count (< 50,000/cumm vs > 50,000). We further confirmed that IL1R1, BCAR3, KCNH2, PIR, and ZDHHC23 were differentially expressed in a larger cohort of ETV6-RUNX1-negative BP-ALL patient samples. Statistical analysis demonstrated that expression levels of these genes could accurately categorize high and low WBC count subjects using two independent patient sets, representing positive and negative ETV6-RUNX1 cases. Further studies in leukemia cell line models will better delineate the role of these genes in regulating the white blood cell count and potentially identify new therapeutic targets.

Extracorporeal membrane oxygenation outcomes in children with hemophagocytic lymphohistiocytosis

Introduction: Pediatric patients with hemophagocytic lymphohistiocytosis (HLH) may develop refractory respiratory or cardiac failure that warrants consideration for extracorporeal membrane oxygenation (ECMO) support. The purposes of this study were to describe the use and outcomes of ECMO in pediatric HLH patients, to identify risk factors for hospital mortality and to compare their ECMO use and outcomes to the ECMO population as a whole. Methods: Pediatric patients (⩽ 18 years) with a diagnosis of HLH in the Extracorporeal Life Support Organization (ELSO) Registry were included. Results: Between 1983 and 2014, data for 30 children with HLH were available in the ELSO registry and all were included in this study. All cases occurred in the last decade. Of the 30 HLH patients, 24 (80%) had a respiratory indication for ECMO and six (20%) had a cardiac indication (of which 4 were E-CPR and 2 cardiac failure). Of the 24 respiratory ECMO patients, 63% were placed on VA ECMO. Compared with all pediatric patients in the ELSO registry during the study period (n=17,007), HLH patients had worse hospital survival (non-HLH 59% vs HLH 30%, p=0.001). In pediatric HLH patients, no pre-ECMO risk factors for mortality were identified. The development of a hemorrhagic complication on ECMO was associated with decreased mortality (p=0.01). Comparing HLH patients with respiratory failure to patients with other immune compromised conditions, the overall survival rate is similar (HLH 38% vs. non-HLH immune compromised 31%, p=0.64). Conclusions: HLH is an uncommon indication for ECMO and these patients have increased mortality compared to the overall pediatric ECMO population. These data should be factored into decision-making when considering ECMO for pediatric HLH patients.