Publications by authors named "Eric Lowe"

26 Publications

  • Page 1 of 1

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

Eur J Cancer 2021 Nov 15;157:198-213. Epub 2021 Sep 15.

Hospital for Sick Children, Toronto, Canada.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
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http://dx.doi.org/10.1016/j.ejca.2021.08.022DOI Listing
November 2021

Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1.

Blood 2021 Jul;137(26):3595-3603

Center for Cancer and Immunology Research, Department of Pediatrics, Children's National Hospital and The George Washington University, Washington, DC.

Approximately 30% of pediatric patients with anaplastic large cell lymphoma (ALCL) relapse. Although brentuximab vedotin has demonstrated excellent activity in ALCL, it has not been used for newly diagnosed patients. Children's Oncology Group (COG) trial ANHL12P1 determined the toxicity and efficacy of brentuximab vedotin with chemotherapy in children with newly diagnosed nonlocalized anaplastic large cell lymphoma kinase (ALK)+/CD30+ ALCL. From 2013 to 2017, 68 children with ALK+ ALCL were enrolled and received brentuximab vedotin. All patients received 5-day prophase, followed by 6 cycles of chemotherapy. Brentuximab vedotin was given on day 1 of each of the 6 cycles. Of the 67 patients eligible for toxicity evaluation, 66 completed all 6 cycles of chemotherapy, resulting in 399 evaluable cycles. There were no toxic deaths, no case of progressive multifocal leukoencephalopathy syndrome, and no case of grade 3 or 4 neuropathy. The 2-year event-free survival (EFS) was 79.1% (95% confidence interval [CI], 67.2-87.1). The 2-year overall survival (OS) was 97.0% (95% CI, 88.1-99.2). Fourteen patients relapsed. Eleven of 14 (79%) relapses occurred within 10 months of diagnosis; only 1 patient (1.5%) relapsed during therapy. Quantitative reverse transcription polymerase chain reaction for NPM-ALK at baseline (minimal disseminated disease) demonstrated prognostic value for EFS (P = .0004). Overall, the addition of brentuximab vedotin to standard chemotherapy does not add significant toxicity or alter the desired interval between cycles. The addition of brentuximab vedotin prevented relapses during therapy, and the OS and EFS estimates compare favorably with results obtained using conventional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01979536.
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http://dx.doi.org/10.1182/blood.2020009806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462406PMC
July 2021

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK.

Br J Haematol 2019 06 25;185(6):1043-1054. Epub 2019 Jan 25.

Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, UK.

Anaplastic large cell lymphoma (ALCL) is a T cell Non-Hodgkin Lymphoma that mainly presents in paediatric and young adult patients. The majority of cases express a chimeric fusion protein resulting in hyperactivation of anaplastic lymphoma kinase (ALK) as the consequence of a chromosomal translocation. Rarer cases lack expression of ALK fusion proteins and are categorised as ALCL, ALK-. An adapted regimen of an historic chemotherapy backbone is still used to this day, yielding overall survival (OS) of over 90% but with event-free survival (EFS) at an unacceptable 70%, improving little over the past 30 years. It is clear that continued adaption of current therapies will probably not improve these statistics and, for progress to be made, integration of biology with the design and implementation of future clinical trials is required. Indeed, advances in our understanding of the biology of ALCL are outstripping our ability to clinically translate them; laboratory-based research has highlighted a plethora of potential therapeutic targets but, with high survival rates combined with a scarcity of funding and patients to implement paediatric trials of novel agents, progress is slow. However, advances must be made to reduce the side-effects of intensive chemotherapy regimens whilst maintaining, if not improving, OS and EFS.
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http://dx.doi.org/10.1111/bjh.15763DOI Listing
June 2019

Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide).

J Med Chem 2018 12 11;61(24):11127-11143. Epub 2018 Dec 11.

Kezar Life Sciences , 4000 Shoreline Court, Suite 300 , South San Francisco , California 94080 , United States.

Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model. These and additional findings toward optimized solubility led the design and selection of KZR-616 disclosed here and presently in clinical trials for treatment of rheumatic disease.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01201DOI Listing
December 2018

Spontaneous Remission of Monosomy 7 Six Years After Diagnosis.

J Pediatr Hematol Oncol 2019 Apr;41(3):e177-e178

Departments of Pediatrics.

Monosomy 7 may be a poor prognostic indicator in pediatric myelodysplastic syndrome. There are case reports of children with monosomy 7 who undergo spontaneous remission 2 to 24 months after diagnosis. We report a case of a child with bone marrow failure and monosomy 7 who underwent spontaneous remission 75 months after diagnosis. The patient had no exposure to chemotherapeutic or immunosuppressive agents. The patient did not receive chemotherapy or other treatment during the 75 months. Despite remaining positive for monosomy 7, he never developed myelodysplasia or acute myeloid leukemia. Spontaneous remission of monosomy 7 may occur years after diagnosis in some patients.
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http://dx.doi.org/10.1097/MPH.0000000000001194DOI Listing
April 2019

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.

ACS Med Chem Lett 2017 Apr 9;8(4):413-417. Epub 2017 Mar 9.

Kezar Life Sciences, 300 Utah Avenue, Suite 105, South San Francisco, California 94080, United States.

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().
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http://dx.doi.org/10.1021/acsmedchemlett.6b00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392757PMC
April 2017

Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells.

Mol Cell Proteomics 2016 10 8;15(10):3233-3242. Epub 2016 Aug 8.

From the ‡Department of Biochemistry, Vanderbilt University School of MedicineNashville, Tennessee;

Carfilzomib (CFZ) is a second-generation proteasome inhibitor that is Food and Drug Administration and European Commission approved for the treatment of relapsed or refractory multiple myeloma. CFZ is an epoxomicin derivative with an epoxyketone electrophilic warhead that irreversibly adducts the catalytic threonine residue of the β5 subunit of the proteasome. Although CFZ produces a highly potent, sustained inactivation of the proteasome, the electrophilic nature of the drug could potentially produce off-target protein adduction. To address this possibility, we synthesized an alkynyl analog of CFZ and investigated protein adduction by this analog in HepG2 cells. Using click chemistry coupled with streptavidin based IP and shotgun tandem mass spectrometry (MS/MS), we identified two off-target proteins, cytochrome P450 27A1 (CYP27A1) and glutathione S-transferase omega 1 (GSTO1), as targets of the alkynyl CFZ probe. We confirmed the adduction of CYP27A1 and GSTO1 by streptavidin capture and immunoblotting methodology and then site-specifically mapped the adducts with targeted MS/MS methods. Although CFZ adduction of CYP27A1 and GSTO1 in vitro decreased the activities of these enzymes, the small fraction of these proteins modified by CFZ in intact cells should limit the impact of these off-target modifications. The data support the high selectivity of CFZ for covalent modification of its therapeutic targets, despite the presence of a reactive electrophile. The approach we describe offers a generalizable method to evaluate the safety profile of covalent protein-modifying therapeutics.
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http://dx.doi.org/10.1074/mcp.M116.059709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054346PMC
October 2016

Plasmacytoma-like Posttransplant Lymphoproliferative Disorder in a Pediatric Heart Transplant Recipient.

J Pediatr Hematol Oncol 2016 Mar;38(2):e71-4

*Department of Pediatrics, Division of Hematology-Oncology ‡Department of Pediatrics, Division of Cardiology, University of Virginia Children's Hospital, Charlottesville, VA †Department of Laboratory Medicine, University of California, San Francisco, CA §Department of Pediatrics, Division of Cardiology, Children's Hospital at Montefiore, Bronx, NY ∥Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital of the King's Daughters, Norfolk, VA.

Posttransplant lymphoproliferative disorder (PTLD) is a diversely manifesting group of lymphoid or plasmacytic proliferations found in solid organ and bone marrow transplant recipients. PTLD occurs as a result of immunosuppression and is often driven by the Epstein Barr virus. Although most commonly of B-cell origin, similar to B-cell lymphomas, PTLD can rarely present as a plasmacytic process, resembling multiple myeloma. Although more common in adults, 8 cases of plasmacytoma-like PTLD have been reported in pediatric renal and combined small bowel-liver transplant recipients. Here, we present a rare report of a plasmacytoma-like PTLD case in a pediatric heart transplant recipient.
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http://dx.doi.org/10.1097/MPH.0000000000000501DOI Listing
March 2016

Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group.

Pediatr Blood Cancer 2014 Dec 23;61(12):2236-42. Epub 2014 Aug 23.

Division of Pediatric Hematology-Oncology, Hospital for Sick Children, Toronto, Ontario.

Background: Optimal therapy for children and adolescents with advanced stage anaplastic large cell lymphoma (ALCL) is unknown. ANHL0131 examined whether a maintenance regimen including vinblastine compared to the standard APO (doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) regimen would result in superior event-free survival.

Procedure: One hundred and twenty five eligible patients were enrolled. Induction was identical for both arms. Post induction patients were randomized to receive APO with vincristine every 3 weeks or a regimen that substituted vincristine with weekly vinblastine (APV).

Results: There was no difference between the patients randomized to the APO versus APV arms in either event free survival (EFS) or overall survival (OS) (three year EFS 74% vs. 79%, P = 0.68 and three years OS of 84% vs. 86%, P = 0.87, respectively). Patients in the APV arm required dose reduction secondary to myelosuppression and had a higher incidence of neutropenia as well as infection with neutropenia compared to those in the APO arm (P < 0.001, P = 0.019, respectively).

Conclusions: Treatment with weekly vinblastine instead of every three week vincristine as part of multi-agent maintenance therapy did not result in improvement in EFS or OS. Weekly vinblastine was associated with increased toxicity. (ClinicalTrials.gov Identifier NCT00059839).
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http://dx.doi.org/10.1002/pbc.25187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682366PMC
December 2014

PhyloSift: phylogenetic analysis of genomes and metagenomes.

PeerJ 2014 9;2:e243. Epub 2014 Jan 9.

Department of Evolution and Ecology, University of California , Davis, CA , United States of America ; Department of Medical Microbiology and Immunology, University of California , Davis, CA , United States of America.

Like all organisms on the planet, environmental microbes are subject to the forces of molecular evolution. Metagenomic sequencing provides a means to access the DNA sequence of uncultured microbes. By combining DNA sequencing of microbial communities with evolutionary modeling and phylogenetic analysis we might obtain new insights into microbiology and also provide a basis for practical tools such as forensic pathogen detection. In this work we present an approach to leverage phylogenetic analysis of metagenomic sequence data to conduct several types of analysis. First, we present a method to conduct phylogeny-driven Bayesian hypothesis tests for the presence of an organism in a sample. Second, we present a means to compare community structure across a collection of many samples and develop direct associations between the abundance of certain organisms and sample metadata. Third, we apply new tools to analyze the phylogenetic diversity of microbial communities and again demonstrate how this can be associated to sample metadata. These analyses are implemented in an open source software pipeline called PhyloSift. As a pipeline, PhyloSift incorporates several other programs including LAST, HMMER, and pplacer to automate phylogenetic analysis of protein coding and RNA sequences in metagenomic datasets generated by modern sequencing platforms (e.g., Illumina, 454).
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http://dx.doi.org/10.7717/peerj.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897386PMC
January 2014

Anaplastic large cell lymphoma in children and adolescents.

Pediatr Hematol Oncol 2013 Sep 12;30(6):509-19. Epub 2013 Jun 12.

Division of Pediatric Hematology-Oncology, Children's Hospital of the Kings Daughters, Norfolk, Virginia 25507, USA.

Anaplastic Large Cell Lymphoma (ALCL) is the most common mature T-cell neoplasm in children and adolescents. ALCLs comprise approximately 15% of all non-Hodgkin lymphomas (NHL) in children and adolescents and commonly present with advanced systemic disease. Dissimilar from ALCL in adults, ALCL in children is nearly universally anaplastic large cell lymphoma kinase (ALK) positive. Despite the relative rarity of the disease, a great deal of insight into the pathogenesis of ALCL has been learned by researching the essential oncogenic role of ALK. Many different treatment strategies have been utilized with similar event free survival (EFS) rates of 65-75%. This review will provide an overview of the pathology, clinical features, prognostics factors, and treatment for children and adolescents with ALK positive ALCL.
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http://dx.doi.org/10.3109/08880018.2013.805347DOI Listing
September 2013

Potential therapies for anaplastic lymphoma kinase-driven tumors in children: progress to date.

Paediatr Drugs 2013 Jun;15(3):163-9

Division of Pediatric Hematology-Oncology, Children's Hospital of the King's Daughters, Norfolk, VA, USA.

Anaplastic lymphoma kinase (ALK) is an oncogenic tyrosine kinase that is deregulated due to a variety of molecular mechanisms in pediatric cancer. They include chromosomal translocations, activation mutations, and gene amplifications. Since the initial discovery of ALK as an oncogenic tyrosine kinase involved in the chromosomal translocation t(2, 5)(p23;q35) in 1994, more than 20 translocation partners of ALK have been identified in various cancers. Furthermore, deregulation of ALK tyrosine kinase activity is critical for the pathogenesis of several other pediatric tumors, including neuroblastomas and inflammatory myofibroblastic tumors. The recent discovery of ALK translocations in adult lung cancer patients (non-small cell lung cancer) has accelerated the development of inhibitors of ALK tyrosine kinase as therapeutic agents. While excellent clinical response has been observed in many patients, the acquisition of clinical resistance to ALK inhibition highlights the need for development of second-generation ALK kinase inhibitors and/or combination therapies that target downstream signaling mediators or antibody drug conjugates. This article provides an update on the spectrum of ALK-driven tumors in the pediatric population and the potential therapies which target these tumors.
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http://dx.doi.org/10.1007/s40272-013-0027-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267854PMC
June 2013

Chronic myelogenous leukemia in a 4-year-old boy.

Eur J Haematol 2013 Sep 15;91(3):286. Epub 2013 Jun 15.

Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.

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http://dx.doi.org/10.1111/ejh.12143DOI Listing
September 2013

MALT lymphoma of the lip.

Pediatr Blood Cancer 2011 Apr 1;56(4):683-4. Epub 2010 Dec 1.

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http://dx.doi.org/10.1002/pbc.22895DOI Listing
April 2011

Clinicopathologic features of histiocytic lesions following ALL, with a review of the literature.

Pediatr Dev Pathol 2010 May-Jun;13(3):225-37

Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

We describe the clinicopathologic features of 15 patients who had histiocytic lesions that followed acute lymphoblastic leukemia (ALL). Twenty-one separate histiocytic lesions were evaluated that covered a wide spectrum, some conforming to the usual categories of juvenile xanthogranulomas (5), Langerhans' cell histiocytosis (1), Langerhans' cell sarcoma (4), Rosai-Dorfman disease (1), and histiocytic sarcoma (4). Most were atypical for the category by histology, phenotype, or abnormally high turnover rate. Seven low-grade lesions defied easy categorization and were characterized only as "atypical histiocytic lesion" following ALL. For those evaluated, the molecular signature of the prior leukemia was present in the histiocytic lesion. In 3 of 15 patients, the leukemia and histiocytic lesion shared immunoglobulin H or monoclonal TCR gene rearrangements and, in 4 of 15 patients, clonal identity was documented by fluorescence in situ hybridization. Four patients died of progressive disease, 3 of whom had histiocytic sarcoma and 1 who had an atypical lesion. One patient died of recurrent ALL. The other 10 patients are alive, 7 after recurrences and treatment with surgery and/or chemotherapy. The post-ALL lesions are more aggressive than their native counterparts, but despite the demonstration of the presence of the leukemia signature in 7 of 15 patients, the prognosis is generally favorable, except for patients with histiocytic sarcoma. It remains unclear whether the histiocytic lesions arise as a line from the original ALL or whether transdifferentiation is involved.
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http://dx.doi.org/10.2350/09-03-0622-OA.1DOI Listing
September 2010

Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941.

Pediatr Blood Cancer 2009 Mar;52(3):335-9

Division of Pediatric Hematology-Oncology, Children's Hospital of the King's Daughters, Norfolk, Virginia 23507, USA.

Background: Anaplastic large cell lymphoma (ALCL) is characterized by advanced disease at presentation (70-80% of pediatric cases) and accounts for 10-15% of all childhood lymphomas. Treatment strategies for pediatric ALCL vary from short pulse B-NHL chemotherapy to prolonged leukemia like therapy. The optimal treatment strategy is unknown.

Methods: CCG-5941 used a compressed aggressive multiagent T-cell lineage chemotherapy regimen consisting of a 3-week induction therapy (vincristine, prednisone, cyclophosphamide, daunomycin, asparaginase) followed by a 3-week consolidation period (vincristine, prednisone, etoposide, 6-thioguanine, cytarabine, asparaginase, methotrexate) followed by six courses of maintenance chemotherapy at 7-week intervals (cyclophosphamide, 6-thioguanine, vincristine, prednisone, doxorubicin, asparaginase, methotrexate etoposide, cytarabine). Total therapy was 48 weeks.

Results: Eighty-six children (male 56%, female 44%) with non-localized ALCL (CD30+) were treated. The majority of tumors were positive for ALK (90%) and of T lineage (83%). Extranodal disease was common (mediastinum 35%, skin 15%, lung 14%, bone 12%, bone marrow 13%, liver 6%, and other viscera 17%). Grade 4 neutropenia occurred in 82% of patients. The 5-year EFS was 68% (95% CI of 57-78%) and the 5-year OS was 80% (95% CI of 69-87%). There were 21 relapses and 4 toxic deaths as first events. Relapse occurred early with 17 (81%) relapses occurring within 2 years of diagnosis and 12 (57%) while receiving therapy. Univariate analysis for risk factors only identified bone marrow involvement predicting lower EFS (P = 0.03).

Conclusions: CCG-5941 demonstrated efficacy similar to previously reported regimens but with significant hematologic toxicity.
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http://dx.doi.org/10.1002/pbc.21817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769495PMC
March 2009

Doing what we can with what we have.

Ann Emerg Med 2008 Mar;51(3):328-9

Department of Emergency Medicine, Maine Medical Center, Portland, ME, USA.

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http://dx.doi.org/10.1016/j.annemergmed.2007.09.009DOI Listing
March 2008

Evaluation of responses of an air medical helicopter program during a comprehensive emergency response drill.

Air Med J 2007 May-Jun;26(3):139-43

Department of Traumatology and Emergency Medicine, Hartford Hospital, Hartford, Connecticut 06102-5037, USA.

Introduction: Participation of air medical service programs in emergency response drills can reveal important information regarding preparedness. This article reviews one program's participation in a drill, the evaluation methods used to assess the program's response, and the findings of the drill evaluation.

Methods: A comprehensive evaluation method was developed and completed for the drill. The responses that would be required by LIFE STAR Communications, the entity charged with communication and coordination of LIFE STAR, Hartford Hospital's air medical helicopter program, were evaluated.

Results: Deficiencies revealed during the drill included requests from emergency responders that were not covered by current policies.

Conclusions: The evaluation of LIFE STAR Communications during a drill revealed specific problems that would have gone unrecognized without participation in the emergency preparedness exercise. Air medical services should participate and be evaluated in drills to enhance preparedness through the clarification of responsibilities and the practice of protocol and policy directives.
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http://dx.doi.org/10.1016/j.amj.2006.08.009DOI Listing
July 2007

Aggressive Digital Papillary Adenocarcinoma in a 15-year-old Female.

J Pediatr Hematol Oncol 2006 Aug;28(8):529-30

Department of Hematology-Oncology, Children's Hospital of the King's Daughters, Norfolk, VA 23507, USA.

Aggressive digital papillary adenocarcinoma is a rare neoplasm of eccrine sweat gland origin that typically presents as a mass on a finger, toe, or the adjacent skin. Less than 100 cases have been reported. The majority of these cases are described in males in their fifth to seventh decade. We report a case of an aggressive digital papillary adenocarcinoma of the right second toe in a 15-year-old white female. A metastatic work-up, computed tomography of the chest, abdomen, pelvis, and a bone scan, was negative. The patient underwent amputation of the right second toe through the metatarsophalangeal joint. Two sentinel lymph nodes were biopsied and found to be negative for metastatic disease. One year after surgery the patient has no evidence of disease recurrence. To our knowledge, this is the youngest reported case of an aggressive digital papillary adenocarcinoma.
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http://dx.doi.org/10.1097/01.mph.0000212969.06125.58DOI Listing
August 2006

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in children and adolescents.

Semin Thromb Hemost 2005 Dec;31(6):717-30

Division of Pediatric Hematology-Oncology, Eastern Virginia Medical School, Children's Hospital of the King's Daughters, Norfolk, Virginia 23507, USA.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are both uncommon disorders that present with a microangiopathic hemolytic anemia and thrombocytopenia. Although for TTP, neurologic manifestations predominate, and in HUS renal dysfunction is virtually always present, there is significant overlap in their clinical presentation. In recent years, tremendous progress has been made in our understanding of the pathogenesis of these disorders. It is now apparent that there are subcategories of both TTP and HUS that can differ in their clinical manifestations, etiology, and management. For instance, although most cases of HUS are due to infection with organisms that produce Shiga-like toxin, other cases may be caused by defined genetic abnormalities. Similarly, TTP is usually caused by genetic or acquired deficiency of the ADAMTS13 enzyme; however, in other cases the relationship with this enzyme remains to be established. Management includes supportive care, plasma transfusions for genetic protein deficiencies, and plasma exchange transfusion for autoimmune TTP.
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http://dx.doi.org/10.1055/s-2005-925478DOI Listing
December 2005

Childhood anaplastic large cell lymphoma has a high incidence of ALK gene rearrangement as determined by immunohistochemical staining and fluorescent in situ hybridisation: a genetic and pathological correlation.

Br J Haematol 2005 Dec;131(5):624-7

Department of Pathology, University of Utah Health Sciences and ARUP Institute, Salt Lake City, UT 84132, USA.

Anaplastic large cell lymphoma (ALCL) comprises 10-15% of childhood non-Hodgkin lymphomas (NHL). Systemic ALCL is highly associated with anaplastic lymphoma kinase (ALK) gene translocations with over-expression of ALK protein. We studied ALK rearrangements using fluorescence in situ hybridisation (FISH) and ALK immunohistochemical staining in 43 paediatric systemic ALCLs. FISH (performed on 35 cases) identified a translocation in 29 cases (83%). Immunohistochemistry identified ALK over-expression in 42/43 cases (97%) with the single ALK-negative case demonstrating an ALK rearrangement by FISH, indicating 100% incidence of ALK translocations.
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http://dx.doi.org/10.1111/j.1365-2141.2005.05808.xDOI Listing
December 2005

Cold sensitivity as a new side effect after sympathicotomy for hyperhidrosis.

Ann Thorac Surg 2005 Dec;80(6):2356-8

University of Connecticut School of Medicine, Farmington, Connecticut, USA.

Extremity cold sensitivity is a previously unreported side effect of thoracoscopic sympathicotomy. We report a case of a young man who underwent thoracoscopic sympathicotomy for hyperhidrosis, after which cold sensitivity developed in his sympathicotomized right hand and arm. When exposed to cold, the right hand and forearm become numb and the skin temperature drops to uncomfortable levels, while the left extremity remains comfortably warm.
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http://dx.doi.org/10.1016/j.athoracsur.2004.07.003DOI Listing
December 2005

Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis.

Pediatr Blood Cancer 2005 Jul;45(1):10-5

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.

Background: The optimal management of childhood acute lymphoblastic leukemia (ALL) with hyperleukocytosis is unclear, largely because the risk of leukostasis-related complications is poorly characterized.

Procedure: We reviewed the presenting characteristics, initial management, and frequency and type of complications in all children seen at St. Jude Children's Research Hospital with previously untreated ALL and an initial leukocyte count >200 x 10(9)/L.

Results: A total of 178 children, representing 8% of all children with ALL, had an initial leukocyte count >200 x 10(9)/L; 67 patients had a leukocyte count >400 x 10(9)/L. Sixteen patients (9%) had neurological complications with 12 of these patients experiencing symptoms at presentation. Four patients (2%), all with initial leukocyte counts >400 x 10(9)/L, suffered a CNS hemorrhage. Pulmonary leukostasis occurred in 11 patients (6%). The degree of hyperleukocytosis was significantly predictive of neurological (P = 0.006) and respiratory (P = 0.014) complications. The majority of complications occurred at presentation. Cytoreduction (94 patients) decreased the leukocyte count but delayed initiation of chemotherapy (P = 0.013).

Conclusions: Serious leukostasis-related complications are relatively uncommon in childhood ALL and most occur at presentation. Their incidence increases in proportion to the leukocyte count. A large subset of cases can be managed successfully without cytoreduction. Cytoreduction may be considered for patients with leukocyte counts >400 x 10(9)/L or patients who have complications at presentation.
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http://dx.doi.org/10.1002/pbc.20178DOI Listing
July 2005

Anemia and a large abdominal tumor in an adolescent.

Pediatr Blood Cancer 2004 Feb;42(2):200-4

Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

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http://dx.doi.org/10.1002/pbc.10388DOI Listing
February 2004

T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation.

Br J Haematol 2003 Oct;123(2):323-6

Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.

Natural killer (NK) cell alloreactivity resulting from killer immunoglobulin-like receptor (KIR) ligand incompatibility improves outcomes in patients receiving extensively T-cell-depleted bone marrow (BM) grafts. Patients with KIR ligand incompatibility are at risk for donor T-cell alloreactivity. We investigated the relative significance of NK-cell and T-cell alloreactivity in 105 paediatric patients who received a minimally T-cell-depleted human leucocyte antigen-non-identical BM transplantation. Donor NK-cell incompatibility did not improve patient outcome [engraftment, graft-versus-host disease (GVHD), relapse or overall survival]. In contrast, donor T-cell incompatibility was a risk factor for acute GVHD, chronic GVHD and death. Thus, T-cell alloreactivity dominated that of NK cells in minimally T-cell-depleted grafts.
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http://dx.doi.org/10.1046/j.1365-2141.2003.04604.xDOI Listing
October 2003

Idiopathic thrombocytopenic purpura diagnosed during the second decade of life.

J Pediatr 2002 Aug;141(2):253-8

Division of Hematology-Oncology, Department of Pediatrics, the University of Texas Southwestern Medical Center at Dallas, Texas, USA.

Objective: To retrospectively review our institutional experience of adolescents with idiopathic thrombocytopenic purpura (ITP).

Study Design: Medical record review of all patients diagnosed with ITP between the ages of 10 and 18 years seen at our center from January 1976 to March 2000.

Results: Data were collected from 126 patients. Of the evaluable 110 cases, 63 (57%) satisfied the criteria for chronic ITP, 30 (27%) for acute ITP, and 17 (15%) were uncertain. Sex distribution and mean ages were similar in all 3 groups. Platelet count at presentation was higher in patients with chronic ITP. Splenectomy was performed in 24 patients, with 17 (77%) of 22 having normal platelet counts at last follow-up. Outcome for the nonsplenectomized patients with chronic ITP included normalization of platelet count (n = 4), minimal or no bleeding without treatment (n = 29), treatment for ongoing symptoms (n = 5), and unknown (n = 1). Two patients died, 1 from intracranial hemorrhage and 1 from Escherichia coli sepsis and pulmonary hemorrhage.

Conclusions: Patients 10 to 18 years of age with ITP are more likely than younger children to have chronic disease. Many patients with ITP recover without drug therapy or need for splenectomy. ITP in adolescents shares features of both childhood and adult ITP.
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http://dx.doi.org/10.1067/mpd.2002.125909DOI Listing
August 2002
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