Publications by authors named "Allen R Chen"

52 Publications

More precisely defining risk peri-HCT in pediatric ALL: pre- vs post-MRD measures, serial positivity, and risk modeling.

Blood Adv 2019 11;3(21):3393-3405

Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA.

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
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http://dx.doi.org/10.1182/bloodadvances.2019000449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855112PMC
November 2019

Understanding CancelRx: Results of End-to-End Functional Testing, Proactive Risk Assessment, and Pilot Implementation.

Appl Clin Inform 2019 03 22;10(2):336-347. Epub 2019 May 22.

Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.

Background: CancelRx allows prescribers to send electronic cancellation messages to pharmacies when medications are discontinued. Little is known about its functionality and impact on clinical workflows.

Objectives: To understand CancelRx functionality, its potential impact on workflows and medication safety risks, and to develop mitigating strategies for risks introduced by implementation.

Methods: We conducted direct observations and semi-structured interviews to develop CancelRx use cases and assessed CancelRx in an end-to-end test environment, proactive risk assessment, and pilot implementation from April 16 to July 15, 2018.

Results: E-cancellations were sent upon discontinuation of e-prescriptions written within the electronic health record (EHR), but not other medications (e.g., printed prescriptions) and could be initiated by nonprescribers. In our proactive risk assessment, CancelRx implementation eliminated five of seven failure modes in outpatient prescribing to Johns Hopkins pharmacies, but introduced new risks, including (1) failure to act if an e-cancellation was not sent or was unsuccessful; (2) failure to cancel all prescriptions for a medication; (3) errors in manual matching; and (4) erroneous medication cancellations. We identified potential mitigation strategies for these risks. During pilot implementation, 92.4% (428/463) of e-cancellations had confirmed approval by the receiving pharmacy, while 4.5% (21/463) were denied, and 3.0% (14/463) had no e-cancellation response. Among e-cancellations received by the pilot pharmacy, 1.7% (7/408) required manual matching by pharmacy staff. Based on performance in testing, 73.4% (340/463) of completed e-cancellations would be expected to generate an in-basket message, including 21 (6.2%) denials and 319/340 (93.8%) approvals with a note from the pharmacy.

Conclusion: CancelRx is an important functionality with the potential to decrease adverse events due to medication errors. However, changes in implementation in our EHR and pharmacy software and enhancements in the CancelRx standard are needed to maximize safety and usability. Further studies are needed to evaluate the impact of e-cancellation on medication safety.
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http://dx.doi.org/10.1055/s-0039-1688698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531208PMC
March 2019

Automated E-mail Reminders Linked to Electronic Health Records to Improve Medication Reconciliation on Admission.

Pediatr Qual Saf 2018 Sep-Oct;3(5):e109. Epub 2018 Sep 19.

Department of Pediatrics, Division of General Pediatrics and Adolescent Medicine, Baltimore, MD.

Introduction: Medication reconciliation can reduce medication discrepancies, errors, and patient harm. After a large academic hospital introduced a medication reconciliation software program, there was low compliance with electronic health record documentation of home medication reconciliation. This quality improvement project aimed to improve medication reconciliation on admission in 4 pediatric inpatient units by 50% over 3 months.

Methods: We used Lean Sigma methodology to observe medication reconciliation processes; interview residents, nurses, pharmacists, and families; and perform swim lane process mapping and Ishikawa Cause and Effect analysis. The improvement plan included education and automated e-mails sent to admitting residents who had not completed medication reconciliation within 24 hours of admission. The daily percentage of patients without medication reconciliation within 24 hours of admission, indicated by the presence of old prescriptions in Sunrise Prescription Writer (RxWriter) (Allscripts Healthcare Solutions, Chicago, Ill.) from prior admissions, was assessed from March 2015-June 2016. We constructed statistical process control charts and identified special causes.

Results: Key barriers included lack of knowledge about RxWriter and lack of accountability for completing medication reconciliation. The percentage of patients without medication reconciliation decreased from 32% at baseline to 22% with education ( < 0.001), to 15% with the use of automated e-mail reminders ( < 0.001). We sustained improvement over the following year. Statistical process control testing indicated shifts aligning with each stage of the study.

Conclusion: Provider-tailored, automated e-mail reminders linked to electronic health record with educational training significantly improved resident compliance with use of an electronic tool for documentation of home medication reconciliation on hospital admission.
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http://dx.doi.org/10.1097/pq9.0000000000000109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221599PMC
September 2018

A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas.

Clin Sarcoma Res 2018 5;8:21. Epub 2018 Nov 5.

1Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD USA.

Background: Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.

Methods: Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m monthly).

Results: Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27-799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.

Conclusions: Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted. The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx.
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http://dx.doi.org/10.1186/s13569-018-0107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217787PMC
November 2018

Outcomes of Measurable Residual Disease in Pediatric Acute Myeloid Leukemia before and after Hematopoietic Stem Cell Transplant: Validation of Difference from Normal Flow Cytometry with Chimerism Studies and Wilms Tumor 1 Gene Expression.

Biol Blood Marrow Transplant 2018 10 19;24(10):2040-2046. Epub 2018 Jun 19.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, USC Keck School of Medicine, Los Angeles, CA, USA.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239928PMC
October 2018

Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients.

Biol Blood Marrow Transplant 2017 Dec 12;23(12):2127-2136. Epub 2017 Aug 12.

Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland.

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986177PMC
December 2017

Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies.

Biol Blood Marrow Transplant 2017 Feb 22;23(2):325-332. Epub 2016 Nov 22.

Pediatric Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland.

Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n = 40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/µL of 16 days (range, 13 to 22) and for platelets >20,000/µL without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT.
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http://dx.doi.org/10.1016/j.bbmt.2016.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346464PMC
February 2017

High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia.

J Pediatr Hematol Oncol 2016 11;38(8):627-635

Departments of *Oncology, Division of Pediatric Oncology †Pediatrics, The Division of Hematology ‡Medicine, The Division of Hematology §Pathology, The Division of Transfusion Medicine ¶The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD ∥Department of Pathology and Lab Medicine, The Division of Transfusion Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Objective: Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression.

Study Design: Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis.

Results: Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28).

Conclusions: Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074865PMC
http://dx.doi.org/10.1097/MPH.0000000000000647DOI Listing
November 2016

Tolerance and effectiveness of nivolumab after pediatric T-cell replete, haploidentical, bone marrow transplantation: A case report.

Pediatr Blood Cancer 2017 03 21;64(3). Epub 2016 Sep 21.

Department of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22-year-old female with multiple-relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post-haplo) HSCT. Anti-PD-1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft-versus-host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD.
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http://dx.doi.org/10.1002/pbc.26257DOI Listing
March 2017

A Model for the Departmental Quality Management Infrastructure Within an Academic Health System.

Acad Med 2017 05;92(5):608-613

S.C. Mathews is research fellow, Armstrong Institute for Patient Safety and Quality, and clinical fellow, Division of Gastroenterology, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland. R. Demski is vice president for quality improvement, Armstrong Institute for Patient Safety and Quality, Johns Hopkins Medicine and Johns Hopkins Health System, Baltimore, Maryland. J.E. Hooper is interim director of autopsy and assistant professor of pathology, Johns Hopkins University, Baltimore, Maryland. L.D. Biddison is vice chair for clinical affairs, Department of Medicine, and assistant professor of medicine, Johns Hopkins University, Baltimore, Maryland. S.A. Berry is associate vice chair for quality, safety, and service, and assistant professor of medicine, Johns Hopkins University, Baltimore, Maryland. B.G. Petty is chair, Pharmacy and Therapeutics Committee and Clinical Quality Improvement Committee, and associate professor of medicine, Johns Hopkins University, Baltimore, Maryland. A.R. Chen is vice chair for quality, safety, and service, and associate professor of oncology and pediatrics, Johns Hopkins University, Baltimore, Maryland. P.M. Hill is vice chair for clinical affairs, Emergency Medicine, and associate professor of emergency medicine, Johns Hopkins University, Baltimore, Maryland. M.R. Miller is vice chair for quality and safety, Children's Center, and professor, Departments of Pediatrics and of Health Policy and Management, Johns Hopkins University, Baltimore, Maryland. F.R. Witter is vice chair for quality, safety, and service, and professor of gynecology and obstetrics, Johns Hopkins University, Baltimore, Maryland. L. Allen is chief patient experience officer, Johns Hopkins Hospital, Baltimore, Maryland. E.C. Wick is associate professor of surgery, Johns Hopkins University, Baltimore, Maryland. T.S. Stierer is director of clinical quality, Ambulatory Anesthesia Division, Department of Anesthesiology and Critical Care Medicine, and associate professor of anesthesiology and critical care medicine, Johns Hopkins University, Baltimore, Maryland. L. Paine is director of patient safety, Armstrong Institute for Patient Safety and Quality, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, Maryland. H.A. Puttgen is assistant professor of neurology, Johns Hopkins University, Baltimore, Maryland. R.J. Tamargo is professor of neurosurgery, Johns Hopkins University, Baltimore, Maryland. P.J. Pronovost is senior vice president for quality and safety, Johns Hopkins Medicine, director, Armstrong Institute for Patient Safety and Quality, and professor, Departments of Anesthesiology and Critical Care Medicine, Surgery, and Health Policy and Management, Johns Hopkins University, Baltimore, Maryland.

As quality improvement and patient safety come to play a larger role in health care, academic medical centers and health systems are poised to take a leadership role in addressing these issues. Academic medical centers can leverage their large integrated footprint and have the ability to innovate in this field. However, a robust quality management infrastructure is needed to support these efforts. In this context, quality and safety are often described at the executive level and at the unit level. Yet, the role of individual departments, which are often the dominant functional unit within a hospital, in realizing health system quality and safety goals has not been addressed. Developing a departmental quality management infrastructure is challenging because departments are diverse in composition, size, resources, and needs.In this article, the authors describe the model of departmental quality management infrastructure that has been implemented at the Johns Hopkins Hospital. This model leverages the fractal approach, linking departments horizontally to support peer and organizational learning and connecting departments vertically to support accountability to the hospital, health system, and board of trustees. This model also provides both structure and flexibility to meet individual departmental needs, recognizing that independence and interdependence are needed for large academic medical centers. The authors describe the structure, function, and support system for this model as well as the practical and essential steps for its implementation. They also provide examples of its early success.
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http://dx.doi.org/10.1097/ACM.0000000000001380DOI Listing
May 2017

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide.

Pediatrics 2016 07 16;138(1). Epub 2016 Jun 16.

Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.
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http://dx.doi.org/10.1542/peds.2015-1080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925071PMC
July 2016

Persistent Multiyear Control of Relapsed T-Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report.

Pediatr Blood Cancer 2016 07 14;63(7):1279-82. Epub 2016 Mar 14.

Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

There are few therapeutic options for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T-ALL. We present the case of a now 9-year-old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life.
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http://dx.doi.org/10.1002/pbc.25971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877254PMC
July 2016

Automated Functional Imaging by 2D Speckle Tracking Echocardiography Reveals High Incidence of Abnormal Longitudinal Strain in a Cohort of Pediatric Oncology Patients.

Pediatr Blood Cancer 2016 Jun 10;63(6):1075-80. Epub 2016 Feb 10.

Department of Pediatric Cardiology, Taussig Heart Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: Automated functional imaging (AFI) was introduced to two-dimensional speckle-tracking echocardiography to facilitate strain assessment in the clinical settings. In patients treated with cardiotoxic anthracyclines, AFI may be helpful in the detection of early myocardial injury when left ventricular ejection fraction (LVEF) remains normal.

Methods: We retrospectively assessed feasibility of AFI in 143 echocardiograms on 102 subjects aged 0.4-22 years (mean 12.3) obtained over a 12-month period. We computed a Z-score for apical four-chamber longitudinal strain using published normal data to assess for abnormal strain in patients with and without previous exposure to anthracyclines.

Results: AFI was feasible in 95.1% of echocardiograms, with low inter- and intraobserver variability. There was a statistically significant association between abnormal longitudinal strain Z-score (SZ < -2.0) and depressed LVEF (<55%, P < 0.001). However, 46% of echocardiograms with normal LVEF had abnormal SZ; half of which had no prior anthracycline exposure. The correlation between SZ and LVEF was strongest in subjects exposed to anthracyclines (r(2) = 0.12, P < 0.01). Increasing age was associated with decreasing SZ. Total cumulative dose, after adjusting for age, was inversely associated with SZ (r(2) = 0.42, P < 0.001). Time from last dose of anthracycline had no significant association with SZ.

Conclusions: AFI is highly feasible in the clinical settings. The observed high prevalence of abnormal longitudinal strain in our cohort emphasizes the importance of obtaining baseline measurements prior to anthracycline treatment. The effects of anthracycline on longitudinal strain may be dose and age dependent, with younger children less likely to show abnormalities.
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http://dx.doi.org/10.1002/pbc.25938DOI Listing
June 2016

Alternative-Donor Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide for Nonmalignant Disorders.

Biol Blood Marrow Transplant 2016 May 6;22(5):895-901. Epub 2016 Feb 6.

Pediatric Blood and Marrow Transplantation Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft-versus-host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable with that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted 11 pediatric patients with life-threatening nonmalignant conditions using reduced-intensity conditioning, alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allogeneic HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted.
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http://dx.doi.org/10.1016/j.bbmt.2016.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898048PMC
May 2016

Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders.

Chest 2015 Oct;148(4):1019-1026

Department of Oncology, Baltimore, MD; Department of Pathology, Baltimore, MD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address:

Background: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease.

Methods: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita.

Results: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed.

Conclusions: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.
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http://dx.doi.org/10.1378/chest.15-0825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594621PMC
October 2015

Bringing central line-associated bloodstream infection prevention home: catheter maintenance practices and beliefs of pediatric oncology patients and families.

Jt Comm J Qual Patient Saf 2015 Apr;41(4):177-85

Johns Hopkins University School of Medicine, Baltimore, USA.

Background: A study was conducted to investigate (1) the extent to which best-practice central line maintenance practices were employed in the homes of pediatric oncology patients and by whom, (2) caregiver beliefs about central line care and central line-associated blood stream infection (CLABSI) risk, (3) barriers to optimal central line care by families, and (4) educational experiences and preferences regarding central line care.

Methods: Researchers administered a survey to patients and families in a tertiary care pediatric oncology clinic that engaged in rigorous ambulatory and inpatient CLABSI prevention efforts.

Results: Of 110 invited patients and caregivers, 105 participated (95% response rate) in the survey (March-May 2012). Of the 50 respondents reporting that they or another caregiver change central line dressings, 48% changed a dressing whenever it was soiled as per protocol (many who did not change dressings per protocol also never personally changed dressings); 67% reported the oncology clinic primarily cares for their child's central line, while 29% reported that an adult caregiver or the patient primarily cares for the central line. Eight patients performed their own line care "always" or "most of the time." Some 13% of respondents believed that it was "slightly likely" or "not at all likely" that their child will get an infection if caregivers do not perform line care practices perfectly every time. Dressing change practices were the most difficult to comply with at home. Some 18% of respondents wished they learned more about line care, and 12% received contradictory training. Respondents cited a variety of preferences regarding line care teaching, although the majority looked to clinic nurses for modeling line care.

Conclusions: Interventions aimed at reducing ambulatory CLABSIs should target appropriate educational experiences for adult caregivers and patients and identify ways to improve compliance with best-practice care.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519015PMC
http://dx.doi.org/10.1016/s1553-7250(15)41023-2DOI Listing
April 2015

Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031.

J Clin Oncol 2014 Nov 13;32(32):3651-8. Epub 2014 Oct 13.

Debra L. Friedman, Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, Nashville, TN; Lu Chen and Allen Buxton, Children's Oncology Group, Monrovia, CA; Suzanne Wolden, Memorial Sloan Kettering Cancer Center, New York; Robert E. Hutchison, State University of New York Upstate Medical University, Syracuse; Louis S. Constine, University of Rochester, Rochester, NY; Kathleen McCarten, Thomas J. FitzGerald, and Sandra Kessel, Quality Assurance Review Center, Providence, RI; Pedro A. De Alarcon, University of Illinois College of Medicine, Peoria, IL; Allen R. Chen, Johns Hopkins University, Baltimore, MD; Nathan Kobrinsky, Sanford Medical Center and Roger Maris Cancer Center, Fargo, ND; Peter Ehrlich, C.S. Mott Children's Hospital and University of Michigan, Ann Arbor, MI; and Cindy L. Schwartz, MD Anderson Cancer Center, Houston, TX.

Purpose: The Children's Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used.

Patients And Methods: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT.

Results: Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment.

Conclusion: This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response.
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http://dx.doi.org/10.1200/JCO.2013.52.5410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220044PMC
November 2014

WT1 regulates angiogenesis in Ewing Sarcoma.

Oncotarget 2014 May;5(9):2436-49

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.

Angiogenesis is required for tumor growth. WT1, a protein that affects both mRNA transcription and splicing, has recently been shown to regulate expression of vascular endothelial growth factor (VEGF), one of the major mediators of angiogenesis. In the present study, we tested the hypothesis that WT1 is a key regulator of tumor angiogenesis in Ewing sarcoma. We expressed exogenous WT1 in the WT1-null Ewing sarcoma cell line, SK-ES-1, and we suppressed WT1 expression using shRNA in the WT1-positive Ewing sarcoma cell line, MHH-ES. Suppression of WT1 in MHH-ES cells impairs angiogenesis, while expression of WT1 in SK-ES-1 cells causes increased angiogenesis. Different WT1 isoforms result in vessels with distinct morphologies, and this correlates with preferential upregulation of particular VEGF isoforms. WT1-expressing tumors show increased expression of pro-angiogenic molecules such as VEGF, MMP9, Ang-1, and Tie-2, supporting the hypothesis that WT1 is a global regulator of angiogenesis. We also demonstrate that WT1 regulates the expression of a panel of pro-angiogenic molecules in Ewing sarcoma cell lines. Finally, we found that WT1 expression is correlated with VEGF expression, MMP9 expression, and microvessel density in samples of primary Ewing sarcoma. Thus, our results demonstrate that WT1 expression directly regulates tumor angiogenesis by controlling the expression of a panel of pro-angiogenic genes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058017PMC
http://dx.doi.org/10.18632/oncotarget.1610DOI Listing
May 2014

Factors predictive of relapse of acute leukemia in children after allogeneic hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2014 Jul 30;20(7):1033-9. Epub 2014 Mar 30.

Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.

The presence of minimal residual disease (MRD) before transplantation is the most important prognostic risk factor predictive of post-transplantation relapse in hematologic malignancies. However, MRD alone does not adequately predict relapse in all patients. To improve upon the ability to identify patients likely to relapse, we evaluated risk factors, in addition to MRD, that may be associated with development of post-transplantation relapse. In this single institution, retrospective cohort study of children with acute leukemia or myelodysplastic syndrome who had undergone a first allogeneic transplantation and had pretransplantation MRD evaluation, 40 of 93 patients (43%) experienced relapse. Univariate analysis demonstrated that African American race, high initial white blood cell count, central nervous system (CNS) disease at diagnosis, short first complete remission, nonmyeloablative (NMA) conditioning, lack of remission, and MRD before transplantation were associated with worse relapse-free survival (RFS). In a Cox multivariable analysis, CNS disease (P = .009), lack of remission (P = .01), and NMA conditioning (P = .04) were independently associated with inferior RFS. Among those in a morphologic complete remission who underwent a myeloablative transplantation, having both CNS disease at diagnosis (specifically in acute lymphoblastic leukemia) and MRD positivity was an independent risk factor predictive of relapse, which has not been previously reported. Results from our study support the existence of risk factors complimentary to pretransplantation MRD. Validation in a larger independent homogenous cohort is needed to develop a prognostic tool for clinical use to predict post-transplantation relapse.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471051PMC
July 2014

Feasibility of treating post-transplantation minimal residual disease in children with acute leukemia.

Biol Blood Marrow Transplant 2014 Jul 27;20(7):1000-7. Epub 2014 Mar 27.

Pediatric Oncology, Johns Hopkins University, Baltimore, Maryland.

Outcomes are poor for patients with hematologic malignancies who experience overt relapse after allogeneic hematopoietic stem cell transplantation (HCT). Data on outcomes of post-transplantation minimal residual disease (MRD) are limited. In this single-institution, retrospective cohort analysis of children with acute leukemia and myelodysplastic syndrome, we document the pattern of relapse with a primary focus on outcomes of post-transplantation MRD. Forty of 93 patients (43%) who underwent a first allogeneic HCT and had systematic pretransplantation and post-transplantation MRD evaluations at +30, +60, +90, +180 days and +1 and +2 years post-transplantation experienced relapse. The median time to relapse was 4.8 months post-transplantation, with a median survival of 4 months post-relapse. Despite frequent, systematic, routine post-HCT disease restaging evaluation, 31 patients (78%) presented with overt disease at the time of relapse. Seven patients with acute leukemia who had post-transplantation MRD presented at a median of 1 month post-transplantation. Owing to rapid disease progression or treatment-related mortality, there was no improvement in survival in those patients whose leukemia was detected in a state of MRD post-transplantation. Our results suggest that early intervention strategies targeting post-transplantation MRD for relapse prevention in acute leukemia may not be feasible.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077899PMC
July 2014

Central line maintenance bundles and CLABSIs in ambulatory oncology patients.

Pediatrics 2013 Nov 7;132(5):e1403-12. Epub 2013 Oct 7.

Department of Pediatrics, The Children's Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, NY 10467.

Objective: Pediatric oncology patients are frequently managed with central lines as outpatients, and these lines confer significant morbidity in this immune-compromised population. We aimed to investigate whether a multidisciplinary, central line maintenance care bundle reduces central line-associated bloodstream infections (CLABSIs) and bacteremias in ambulatory pediatric oncology patients.

Methods: We conducted an interrupted time-series study of a maintenance bundle concerning all areas of central line care. Each of 3 target groups (clinic staff, homecare agency nurses, and patient families) (1) received training on the bundle and its importance, (2) had their practice audited, and (3) were shown CLABSI rates through graphs, in-service training, and bulletin boards. CLABSI and bacteremia person-time incidence rates were collected for 23 months before and 24 months after beginning the intervention and were compared by using a Poisson regression model.

Results: The mean CLABSI rate decreased by 48% from 0.63 CLABSIs per 1000 central line days at baseline to 0.32 CLABSIs per 1000 central line days during the intervention period (P = .005). The mean bacteremia rate decreased by 54% from 1.27 bacteremias per 1000 central line days at baseline to 0.59 bacteremias per 1000 central line days during the intervention period (P < .001).

Conclusions: Implementation of a multidisciplinary, central line maintenance care bundle significantly reduced CLABSI and bacteremia person-time incidence rates in ambulatory pediatric oncology patients with central lines. Further research is needed to determine if maintenance care bundles reduce ambulatory CLABSIs and bacteremia in other adult and pediatric populations.
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http://dx.doi.org/10.1542/peds.2013-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813391PMC
November 2013

Bringing central line-associated bloodstream infection prevention home: CLABSI definitions and prevention policies in home health care agencies.

Jt Comm J Qual Patient Saf 2013 Aug;39(8):361-70

Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA.

Background: A study was conducted to investigate health care agency central line-associated bloodstream infection (CLABSI) definitions and prevention policies and pare them to the Joint Commission National Patient Safety Goal (NPSG.07.04.01), the Centers for Disease Control and Prevention (CDC) CLABSI prevention recommendations, and a best-practice central line care bundle for inpatients.

Methods: A telephone-based survey was conducted in 2011 of a convenience sample of home health care agencies associated with children's hematology/oncology centers.

Results: Of the 97 eligible home health care agencies, 57 (59%) completed the survey. No agency reported using all five aspects of the National Healthcare and Safety Network/Association for Professionals in Infection Control and Epidemiology CLABSI definition and adjudication process, and of the 50 agencies that reported tracking CLABSI rates, 20 (40%) reported using none. Only 10 agencies (18%) had policies consistent with all elements of the inpatient-focused NPSG.07.04.01, 10 agencies (18%) were consistent with all elements of the home care targeted CDC CLABSI prevention recommendations, and no agencies were consistent with all elements of the central line care bundle. Only 14 agencies (25%) knew their overall CLABSI rate: mean 0.40 CLABSIs per 1,000 central line days (95% confidence interval [CI], 0.18 to 0.61). Six agencies (11%) knew their agency's pediatric CLABSI rate: mean 0.54 CLABSIs per 1,000 central line days (95% CI, 0.06 to 1.01).

Conclusions: The policies of a national sample of home health care agencies varied significantly from national inpatient and home health care agency targeted standards for CLABSI definitions and prevention. Future research should assess strategies for standardizing home health care practices consistent with evidence-based recommendations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507507PMC
http://dx.doi.org/10.1016/s1553-7250(13)39050-3DOI Listing
August 2013

Ambulatory pediatric oncology CLABSIs: epidemiology and risk factors.

Pediatr Blood Cancer 2013 Nov 23;60(11):1882-9. Epub 2013 Jul 23.

Department of Pediatrics, The Children's Hospital at Montefiore, Bronx, New York.

Background: To compare the burden of central line-associated bloodstream infections (CLABSIs) in ambulatory versus inpatient pediatric oncology patients, and identify the epidemiology of and risk factors associated with ambulatory CLABSIs.

Procedure: We prospectively identified infections and retrospectively identified central line days and characteristics associated with CLABSIs from January 2009 to October 2010. A nested case-control design was used to identify characteristics associated with ambulatory CLABSIs.

Results: We identified 319 patients with central lines. There were 55 ambulatory CLABSIs during 84,705 ambulatory central line days (0.65 CLABSIs per 1,000 central line days (95% CI 0.49, 0.85)), and 19 inpatient CLABSIs during 8,682 inpatient central line days (2.2 CLABSIs per 1,000 central lines days (95% CI 1.3, 3.4)). In patients with ambulatory CLABSIs, 13% were admitted to an intensive care unit and 44% had their central lines removed due to the CLABSI. A secondary analysis with a sub-cohort, suggested children with tunneled, externalized catheters had a greater risk of ambulatory CLABSI than those with totally implantable devices (IRR 20.6, P < 0.001). Other characteristics independently associated with ambulatory CLABSIs included bone marrow transplantation within 100 days (OR 16, 95% CI 1.1, 264), previous bacteremia in any central line (OR 10, 95% CI 2.5, 43) and less than 1 month from central line insertion (OR 4.2, 95% CI 1.0, 17).

Conclusions: In pediatric oncology patients, three times more CLABSIs occur in the ambulatory than inpatient setting. Ambulatory CLABSIs carry appreciable morbidity and have identifiable, associated factors that should be addressed in future ambulatory CLABSI prevention efforts.
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http://dx.doi.org/10.1002/pbc.24677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559846PMC
November 2013

Implementation of a central line maintenance care bundle in hospitalized pediatric oncology patients.

Pediatrics 2012 Oct 3;130(4):e996-e1004. Epub 2012 Sep 3.

Johns Hopkins University School of Medicine, Department of Pediatrics, 2091 Rubenstein Child Health Building, 200 N. Wolfe St, Baltimore MD, 21287, USA.

Objective: To investigate whether a multidisciplinary, best-practice central line maintenance care bundle reduces central line-associated blood stream infection (CLABSI) rates in hospitalized pediatric oncology patients and to further delineate the epidemiology of CLABSIs in this population.

Methods: We performed a prospective, interrupted time series study of a best-practice bundle addressing all areas of central line care: reduction of entries, aseptic entries, and aseptic procedures when changing components. Based on a continuous quality improvement model, targeted interventions were instituted to improve compliance with each of the bundle elements. CLABSI rates and epidemiological data were collected for 10 months before and 24 months after implementation of the bundle and compared in a Poisson regression model.

Results: CLABSI rates decreased from 2.25 CLABSIs per 1000 central line days at baseline to 1.79 CLABSIs per 1000 central line days during the intervention period (incidence rate ratio [IRR]: 0.80, P = .58). Secondary analyses indicated CLABSI rates were reduced to 0.81 CLABSIs per 1000 central line days in the second 12 months of the intervention (IRR: 0.36, P = .091). Fifty-nine percent of infections resulted from Gram-positive pathogens, 37% of patients with a CLABSI required central line removal, and patients with Hickman catheters were more likely to have a CLABSI than patients with Infusaports (IRR: 4.62, P = .02).

Conclusions: A best-practice central line maintenance care bundle can be implemented in hospitalized pediatric oncology patients, although long ramp-up times may be necessary to reap maximal benefits. Further research is needed to determine if this CLABSI rate reduction can be sustained and spread.
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http://dx.doi.org/10.1542/peds.2012-0295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457619PMC
October 2012

Computerized provider order entry in pediatric oncology: design, implementation, and outcomes.

J Oncol Pract 2011 Jul;7(4):218-22

Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.

Purpose: Pediatric oncology is a challenging environment for computerized provider order entry (CPOE). Our goal was to build on the proven safety features of CPOE and facilitate input of expert clinicians.

Methods: A standard, commercially available CPOE system was implemented throughout the hospital. The design of the pediatric oncology implementation was a collaborative effort by a multidisciplinary team of clinicians and information technology experts.

Results: During 9 months of configuration effort, 30 medical logic modules and 110 order sets were developed to support pediatric oncology. The proportion of chemotherapy orders submitted using specific research protocol or standard-of-care order sets increased from 57% to 84% as the number of active order sets grew to 200. The number of medication-related patient safety events decreased 39% after implementation of CPOE in pediatric oncology. Acceptance of the system is high in all clinical disciplines.

Conclusion: Implementation of CPOE required extensive customization but improved patient safety in this highly complex pediatric oncology environment.
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http://dx.doi.org/10.1200/JOP.2011.000344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140441PMC
July 2011

Cyclophosphamide for rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome.

J Pediatr 2011 Feb 21;158(2):337-9. Epub 2010 Aug 21.

Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD 21231, USA.

Patients with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural crest tumor syndrome have poor long-term outcomes. We report a patient who was treated successfully with high-dose cyclophosphamide immunoablation. This experience offers a novel therapeutic approach and an indirect insight into the underlying pathogenesis of this syndrome.
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http://dx.doi.org/10.1016/j.jpeds.2010.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976575PMC
February 2011

Tandem dosing of samarium-153 ethylenediamine tetramethylene phosphoric acid with stem cell support for patients with high-risk osteosarcoma.

Cancer 2010 Dec 16;116(23):5470-8. Epub 2010 Aug 16.

Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA.

Background: Samarium-153 ethylenediamine tetramethylene phosphoric acid (153Sm-EDTMP) is a radiopharmaceutical that has been used to treat osteosarcoma. The authors conducted a phase 2 study to test safety and response of high-risk osteosarcoma to tandem doses of 153Sm-EDTMP and to determine correlation between radiation delivered by low and high administered activities.

Methods: Patients with recurrent, refractory osteosarcoma detectable on standard 99mTc bone scan received a low dose of 153Sm-EDTMP (37.0-51.8 MBq/kg), followed upon count recovery by a second, higher dose (222 MBq/kg). Fourteen days later, patients were rescued with autologous hematopoietic stem cells. The authors assessed response to therapy, performed dosimetry to determine the relationship between administered activity and tumor absorbed dose, and investigated whether changes in 2-(fluorine-18) fluoro-2-deoxy-d-glucose (18F-FDG) tumor uptake upon hematologic recovery reflected disease response.

Results: Nine patients were given tandem doses of 153Sm-EDTMP; 2 received only the initial dose because of disease progression. Six patients experienced radiographic disease stabilization, but this was not considered a response, so the study was terminated early. There was a linear relationship between administered activity and tumor absorbed dose, but there was no correlation between change in 18F-FDG positron emission tomography tumor uptake and tumor absorbed dose or time to progression. The median time to progression for the entire group was 79 days.

Conclusions: Tandem doses of 153Sm-EDTMP were safe for this cohort of heavily pretreated patients with very high-risk disease. The strong correlation between absorbed dose and administered activity within each evaluable patient provides a methodology to individually tailor tandem doses of this agent.
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http://dx.doi.org/10.1002/cncr.25518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991401PMC
December 2010

Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors.

Blood 2010 Nov 29;116(19):4007-15. Epub 2010 Jul 29.

Children's Hospital at Westmead, Sydney, Australia.

Although some trials have allowed matched or single human leukocyte antigen (HLA)-mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.
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http://dx.doi.org/10.1182/blood-2010-01-261958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981549PMC
November 2010

Bone mineral density after bone marrow transplantation in childhood: measurement and associations.

Biol Blood Marrow Transplant 2010 Oct 24;16(10):1451-7. Epub 2010 Apr 24.

Department of Oncology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Unlabelled: This study examined the bone mineral density (BMD) of 46 (median age 16.3, 8-29) survivors of autologous and allogeneic bone marrow transplantation (BMT). Areal (g/m2) BMD was acquired with dual energy x-ray absorptiometry and volumetric (g/cm3) BMD values were calculated. Abnormal BMD was identified in 24% (11/46) of survivors with areal measures and 22% (10/46) with volumetric measures. Comparison of areal and volumetric BMD revealed the measures were highly correlated (r = 0.73, p<0.001) but clinical diagnosis of osteopenia/osteoporosis were not consistent. Volumetric z-scores were higher for 7/8 of the survivors who were < 3rd percentile for height. Associations of BMD and body composition and disease and treatment factors were assessed with multiple linear regression. When controlling for other significant associations and cumulative steroid dose, the body composition measure of fat mass index (FMI) was associated with higher volumetric BMD z-scores (CI: 0.006, 0.193; p = 0.037). CNS irradiation (CI: -1.710,-0.200; p = 0.015), age at time of testing (CI: -0.116, -0.024; p = 0.004) and female sex (CI: -1.375, -0.155; p = 0.015) were associated with lower volumetric BMD z-scores.

Conclusions: Childhood BMT survivors are at risk for diminished BMD. Areal and volumetric DEXA derived measures of BMD are highly correlated and volumetric measures may correct for underestimation of BMD in BMT survivors who are small for age. Survivors who received CNS irradiation, are older and female may be at greater risk for diminished BMD while fat mass is associated with higher BMD in childhood BMT survivors.
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http://dx.doi.org/10.1016/j.bbmt.2010.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933951PMC
October 2010

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

Biol Blood Marrow Transplant 2010 Jul 16;16(7):1005-17. Epub 2010 Feb 16.

Department of Adult Oncology, Harvard Medical School, Boston, MA, USA.

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.
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http://dx.doi.org/10.1016/j.bbmt.2010.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956581PMC
July 2010