Publications by authors named "Melissa Frei-Jones"

11 Publications

  • Page 1 of 1

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.

Pediatr Blood Cancer 2016 12 30;63(12):2123-2130. Epub 2016 Aug 30.

Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri.

Background: Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption.

Procedure: Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125 mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded.

Results: Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9 hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12 hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children.

Conclusions: Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.
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December 2016

Thromboelastography--does it impact blood component transfusion in pediatric heart surgery?

J Surg Res 2016 Jan 10;200(1):21-7. Epub 2015 Jul 10.

Department of Pediatrics, University of Texas Health Sciences Center San Antonio, San Antonio, Texas.

Background: The administration of blood products during pediatric cardiac surgery is common. We sought to determine if thromboelastography (TEG) is a cost-effective tool to reduce blood product transfusion in open pediatric cardiac surgery.

Materials And Methods: A retrospective case-control study was undertaken for 150 pediatric cardiac patients requiring cardiopulmonary bypass from January 2010-May 2012, in a University-affiliated pediatric hospital. Fifty sequential patients operated on when TEG was used were compared with 100 control patients before TEG availability. Groups were matched 2:1 for age and risk adjustment for congenital heart surgery score. Blood product utilization was compared between groups, as were outcomes metrics such as postoperative complications, length of stay, and hospital costs of transfusions.

Results: Demographic variables, risk adjustment for congenital heart surgery score classifications, and cardiopulmonary bypass times were similar between groups. Red cell and plasma transfusion were comparable between groups. TEG patients saw a substantial reduction in the administration of platelet (1 versus 2.2 U; P < 0.0001) and cryoprecipitate (0.7 versus 1.7 U; P < 0.0001) transfusions. A greater than 50% reductions in hospital costs of platelet ($595 versus $1309) and cryoprecipitate ($39 versus $94) transfusions were observed in the TEG group. Mortality, length of stay, ventilator requirements, postoperative bleeding, and thrombotic events were equivalent.

Conclusions: Intraoperative TEG use reduced platelet and cryoprecipitate transfusions without an increase in postoperative complications. TEG is a cost-effective method to direct blood product replacement.
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January 2016

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

N Engl J Med 2014 Sep;371(11):1005-15

From the Departments of Pathology (K.G.R., D.P.-T., Y.-L.Y., K. McCastlain, G.S., J.M., S.-C.C., J.C., N.S.-M., I.I., J.W., J.R.D., C.G.M.), Computational Biology and Bioinformatics (Y.L., J.B., M.R., E.H., P.G., P.N., G.W., X.C., J.Z.), Biostatistics (D.P., C.C.), Pharmaceutical Sciences (S.W.P., M.V.R., W.E.E.), and Oncology (C.-H.P., S.J.), the Pediatric Cancer Genome Project (Y.L., L.D., C.L., M.R., J.E., J.C., K.B., R.S.F., E.H., P.G., P.N., G.W., X.C., D.Y., B.V., H.M., M.V.R., W.E.E., E.M., R.K.W., J.R.D., J.Z., C.G.M.), and Cytogenetics Shared Resource (M.V.), St. Jude Children's Research Hospital, Memphis, TN; the University of New Mexico Cancer Center and School of Medicine, Albuquerque (R.C.H., I-M.C., C.L.W.); the Genome Institute at Washington University (L.D., C.L., R.S.F., E.M., R.K.W.), the Department of Genetics, Washington University School of Medicine (L.D., C.L., R.S.F., E.M., R.K.W.), and Siteman Cancer Center, Washington University (E.M., R.K.W.) - all in St. Louis; Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville (M.D.); the Research Institute at Nationwide Children's Hospital (S.R., A.S., J.M.G.-F.), the Department of Pathology, College of Medicine, Ohio State University (N.A.H.), and Ohio State University Comprehensive Cancer Center (G.M., C.D.B., K. Mrózek, J.K.) - all in Columbus, OH; the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (N.J.W.), Scott and White Hospitals and Clinics and Texas A&M Health Science Center, Temple (G.G.), the University of Texas Health Science Center San Antonio, San Antonio (M.F.-J.), and the Departments of Leukemia and Stem Cell Transplantation, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (S.M.K., M.K.) - all in Texas; Maine Children's Cancer Program, Scarborough (E.C.L.); New York University Cancer Institute, New York (W.L.C.), and the Department of Medicine (Oncology), Albert Einstein

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.

Methods: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.

Results: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.

Conclusions: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).
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September 2014

The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.

Blood 2013 Apr 12;121(15):2943-51. Epub 2013 Feb 12.

Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Breisacher Strasse 117, Freiburg, Germany.

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.
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April 2013

Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease.

Mol Med 2012 Feb 10;18:56-64. Epub 2012 Feb 10.

Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1851, United States of America.

Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-β1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis.
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February 2012

Multi-modal intervention for the inpatient management of sickle cell pain significantly decreases the rate of acute chest syndrome.

Pediatr Blood Cancer 2011 Feb 5;56(2):262-6. Epub 2010 Nov 5.

Department of Genetics, Washington University School of Medicine, St Louis, Missouri, USA.

Introduction: Pain in children with sickle cell disease (SCD) is the leading cause of acute care visits and hospitalizations. Pain episodes are a risk factor for the development of acute chest syndrome (ACS), contributing to morbidity and mortality in SCD. Few strategies exist to prevent this complication.

Methods: We performed a before-and-after prospective multi-modal intervention. All children with SCD admitted for pain during the 2-year study period were eligible. The multi-modal intervention included standardized admission orders, monthly house staff education, and one-on-one patient and caregiver education.

Results: A total of 332 admissions for pain occurred during the study period; 159 before the intervention and 173 during the intervention. The ACS rate declined by 50% during the intervention period 25% (39 of 159) to 12% (21 of 173); P = 0.003. Time to ACS development increased from 0.8 days (0.03-5.2) to 1.7 days (0.03-5.8); P = 0.047. No significant difference was found in patient demographics, intravenous fluid amount administered, frequency of normal saline bolus administration, or cumulative opioid amount delivered in the first 24 hr. Patient controlled analgesia-use was more common after the intervention 52% (82 of 159) versus 73% (126 of 173; P = 0.0001) and fewer patients required changes in analgesic dosing within the first 24 hr after admission (26%, 42 of 159 vs. 16%, 28 of 173; P = 0.015).

Conclusions: A multi-modal intervention to educate and subsequently change physician's behavior likely decreased the rate of ACS in the setting of a single teaching hospital.
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February 2011

Multi-modal intervention and prospective implementation of standardized sickle cell pain admission orders reduces 30-day readmission rate.

Pediatr Blood Cancer 2009 Sep;53(3):401-5

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.

Introduction: The National Association of Children's Hospitals (NACHRI) and the Centers for Medicare and Medicaid Services (CMS) recently introduced 30-day hospital readmission rate as a quality care indicator in children with sickle cell disease (SCD). Based on previous research identifying risk factors for 30-day readmission in our patient population, we designed and implemented a multi-modal intervention to reduce 30-day readmission rate in children with SCD and pain.

Methods: A before-and-after study design was performed to evaluate an intervention containing three components: (1) standardized SCD-pain admission orders; (2) monthly SCD-pain in-service for house physicians for the first 6-months; and (3) continuous patient/caregiver education. Following order implementation, we prospectively collected data on all children admitted for SCD-pain over a 6-month period. We compared the 30-day readmission rate after the intervention to the rate during the same 6-month interval in the previous calendar year prior to the availability of pre-specified SCD-pain orders.

Results: A total of 89 admissions, in 68 individuals, were eligible for the standardized orders during the prospective time period and were compared to 85 admissions in 56 individuals during the control period. Pre-specified SCD-pain orders were used in 93% of eligible admissions during the intervention. Readmission rate within 30 days was lower for the intervention cohort than the control cohort, 11% (10/89) versus 28% (24/85), P = 0.007, 95% CI 0.1-0.7.

Conclusions: A multi-modal intervention was successful in decreasing 30-day hospital readmission rate for children with SCD and pain. Provider education was the most important component of the multi-modal intervention.
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September 2009

Risk factors for hospital readmission within 30 days: a new quality measure for children with sickle cell disease.

Pediatr Blood Cancer 2009 Apr;52(4):481-5

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Background: The National Association of Children's Hospitals and Related Institutions (NACHRI) established hospital readmission within 30 days as a benchmark for quality care in children with Sickle Cell Disease (SCD). Among children with SCD, limited data exists to identify risk factors for readmission and whether they are modifiable.

Procedure: We performed a retrospective cohort study to identify risk factors for readmission. All admissions for children with SCD in a 1-year period were reviewed; cases were defined as children with SCD readmitted within 30 days after their first admission during the study period and controls, children with SCD who were not readmitted.

Results: We identified 30 cases and 70 controls. No difference in demographic data was found between groups. The most common admission and readmission diagnosis was pain, 78 and 70%, respectively. The greatest risk factor for readmission was no outpatient hematology follow-up within 30 days of discharge (OR 7.7, 95% CI 2.4-24.4). A diagnosis of asthma was also a risk factor for readmission (OR 2.9, 95% CI 1.2-7.3). Patients who required supplemental oxygen to maintain saturations in the normal range and were on room air for < or =24 hr at discharge were also more likely to be readmitted (OR 3.3, 95% CI 1.1-9.7). Multivariate analysis identified lack of outpatient follow-up and disease severity, defined as > or =3 admissions in the previous 12 months as predictors for readmission (R(2) = 0.41).

Conclusions: Potentially modifiable risk factors exist to decrease the rate of readmission of children with SCD admitted to the hospital for pain.
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April 2009

Use of thalidomide to diminish growth velocity in a life-threatening congenital intracranial hemangioma.

J Neurosurg Pediatr 2008 Aug;2(2):125-9

Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Infantile or capillary hemangioma is the most common vascular tumor of childhood. The tumors most frequently affect the head and neck area, but rare cases of intracranial lesions have been reported. Their natural history is marked by initial rapid growth velocity followed by a plateau and, in most cases, subsequent involution. Although the lesions are considered benign, 10% of affected children develop life-threatening complications (mortality rate 20-80% in this subgroup). When surgical intervention or other methods of local control are not possible, therapeutic options are limited. Corticosteroids have been the mainstay of therapy but therapeutic response is not predictable and the infectious risk is not negligible. Interferon alpha-2a may also be effective but has significant toxicities. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been implicated in the pathogenesis of hemangiomas, and antiangiogenesis agents are being evaluated in the treatment of these tumors. Thalidomide may be an ideal therapy for life-threatening hemangiomas because it inhibits new blood vessel formation by antagonizing both the bFGF and VEGF pathways and has a more acceptable toxicity profile than other agents. The authors present the case of an infant born with a life-threatening, unresectable intracranial hemangioma in which treatment with thalidomide resulted in a good clinical outcome.
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August 2008

Vaso-occlusive episodes in older children with sickle cell disease: emergency department management and pain assessment.

J Pediatr 2008 Feb 24;152(2):281-5. Epub 2007 Oct 24.

Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Children's Medical Center, Dallas, TX, USA.

Objective: To describe emergency department (ED) management of older children with sickle cell disease (SCD) experiencing a vaso-occlusive episode (VOE) and factors associated with disposition and ED return.

Study Design: We retrospectively reviewed ED visits of children age >/=8 years with SCD over the course of 1 year. Data were collected from the electronic medical record and the SCD database.

Results: VOE was diagnosed 279 times in 105 patients; 45 of the patients had 1 ED visit, 25 had 2 ED visits, and 16 had >/=5 ED visits. The overall admission rate was 178/279 (64%), 166 on the first ED visit and 12 on a return visit within 72 hours. Use of home opioids, duration of VOE, and hemoglobin concentration were not associated with disposition. Discharge after 2 doses of intravenous (IV) morphine occurred in 33 patients. Pain relief after 1 dose, using a FACES scale of 1 to 5, differed significantly between the admitted patients and the discharged patients (1.1 vs 2.5; P < .0001).

Conclusion: Suboptimal pain relief after 1 dose of IV morphine was associated with admission from the ED. Further investigation of pain relief, using validated pain assessment scales, as an outcome in VOE management is warranted.
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February 2008