Publications by authors named "Samir B Kahwash"

41 Publications

Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group.

Blood Adv 2020 12;4(23):6000-6008

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH.

Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.
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http://dx.doi.org/10.1182/bloodadvances.2020002712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724911PMC
December 2020

Unusual red blood cell inclusions in an intravenous drug abuse patient.

Blood Cells Mol Dis 2021 May 9;88:102509. Epub 2020 Oct 9.

Hematopathology division, Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America; Department of Pathology, Nationwide Children's Hospital, Columbus, OH, United States of America.

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http://dx.doi.org/10.1016/j.bcmd.2020.102509DOI Listing
May 2021

Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.

Blood Adv 2020 10;4(20):5050-5061

Hematologics, Inc, Seattle, WA.

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.
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http://dx.doi.org/10.1182/bloodadvances.2020002070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594384PMC
October 2020

Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force.

Cancer 2020 02 29;126(3):593-601. Epub 2019 Oct 29.

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University, Atlanta, Georgia.

Background: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification.

Methods: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL.

Results: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21).

Conclusions: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.
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http://dx.doi.org/10.1002/cncr.32552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489437PMC
February 2020

Separating Lymphoblastic Lymphoma Involving Marrow From Lymphoblastic Leukemia: It is Time to Update the CutOff Number.

J Pediatr Hematol Oncol 2019 Nov;41(8):658-659

Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus, OH.

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http://dx.doi.org/10.1097/MPH.0000000000001588DOI Listing
November 2019

Cytoplasmic Fibrillar Aggregates in Gallbladder Epithelium Are a Frequent Mimic of in Pediatric Cholecystectomy Specimens.

Arch Pathol Lab Med 2019 10 10;143(10):1259-1264. Epub 2019 Apr 10.

From the Department of Pathology, University of Maryland Medical Center, Baltimore (Dr Rose); the Department of Pathology, The Ohio State University Wexner Medical Center, Columbus (Drs C. A. Arnold, Badizadegan, Carter, Conces, Kahwash, Nicol, and M. A. Arnold); and the Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio (Drs Badizadegan, Carter, Conces, Kahwash, Nicol, and M. A. Arnold). Dr Carter is now with Indiana University Health, Southern Indiana Pathologists, Bloomington.

Context.—: is an intracellular parasite associated with gastrointestinal disease in immunocompromised hosts. Although infection has been classically associated with intestinal disease, studies have identified in the gallbladder of immunocompetent patients based on hematoxylin-eosin morphology. Recently, the identity of this histologic finding as has been questioned based on negative results of nucleic acid studies.

Objective.—: To determine the prevalence of this histologic feature in pediatric patients, we retrospectively reviewed all cholecystectomy specimens from a pediatric hospital during a 24-month period.

Design.—: In 180 cholecystectomy specimens, we identified 11 cases (6.1%) with classical histologic features previously described to represent organisms. To further investigate these structures, we retrieved tissue from paraffin-embedded blocks and performed electron microscopy.

Results.—: Ultrastructural examination identified ovoid perinuclear cytoplasmic structures composed of dense fibrillar aggregates rather than organisms. Patients with positive cases were similar in age to controls (positive cases: mean patient age 13.4 years [range, 2-23 years]; negative cases: mean patient age 14.7 years [range, 12 weeks-31 years]; = .35). There was no significant association of this finding with cholelithiasis (54.5% versus 65.1%, = .52), cholesterolosis (0% versus 22.5%, = .12), acute cholecystitis (9.1% versus 10.1%, > .99), or chronic cholecystitis (45.5% versus 66.3%, = .20).

Conclusions.—: To our knowledge, this is the first positive identification of these structures as cytoplasmic fibrillar aggregates rather than parasitic inclusions by ultrastructural examination, and the first study of this histologic finding in pediatric cholecystectomies.
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http://dx.doi.org/10.5858/arpa.2018-0335-OADOI Listing
October 2019

Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group.

J Clin Oncol 2019 04 11;37(10):780-789. Epub 2019 Feb 11.

14 New York University Langone Medical Center, New York, NY.

Purpose: Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome.

Patients And Methods: Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort.

Results: Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes.

Conclusion: Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
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http://dx.doi.org/10.1200/JCO.18.00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440386PMC
April 2019

Monozygotic twins diagnosed simultaneously with RAM immunophenotype acute myeloid leukemia.

Pediatr Transplant 2018 12 15;22(8):e13291. Epub 2018 Sep 15.

Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.

AML with the RAM immunophenotype is associated with extremely poor prognosis. We report a rare case of monozygotic twins presenting simultaneously at the age of 2 years with RAM AML. Each twin underwent a myeloablative 7/10 unrelated umbilical cord blood transplant. Pretransplant Twin A's bone marrow was negative for MRD by flow cytometry (<0.01%) unlike Twin B's bone marrow (0.07%). Twin A is alive in remission 3 years from transplant. Twin B developed primary graft failure, but subsequently rescued with a haploidentical stem cell transplant. However, she relapsed and died 13 months from diagnosis. The twins' clinical courses demonstrate that upfront intensive chemotherapy to achieve negative MRD, followed by allogeneic hematopoietic stem cell transplant as postremission intensification strategy, should be considered in this high-risk AML.
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http://dx.doi.org/10.1111/petr.13291DOI Listing
December 2018

Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma.

Blood Adv 2017 Apr 24;1(11):681-684. Epub 2017 Apr 24.

Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD.

Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
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http://dx.doi.org/10.1182/bloodadvances.2016002618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727814PMC
April 2017

That's Not Supposed to Be There: An Unusual Finding on Urinalysis.

Clin Chem 2017 10;63(10):1660-1661

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH.

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http://dx.doi.org/10.1373/clinchem.2017.271437DOI Listing
October 2017

Acute Myeloid Leukemia with RAM Immunophenotype: A Pediatric Case with Unusual Morphologic Features.

Hematol Rep 2017 Jun 14;9(2):7057. Epub 2017 Jun 14.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML) that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype.
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http://dx.doi.org/10.4081/hr.2017.7057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477472PMC
June 2017

Refractory cytopenias secondary to copper deficiency in children receiving exclusive jejunal nutrition.

Pediatr Blood Cancer 2017 Nov 5;64(11). Epub 2017 May 5.

Division of Pediatric Hematology/Oncology, Hasbro Children's Hospital, Providence, Rhode Island.

Copper deficiency is a known cause of anemia and neutropenia that is easily remedied with copper supplementation. Copper is primarily absorbed in the stomach and proximal duodenum, so patients receiving enteral nutrition via methods that bypass this critical region may be at increased risk for copper deficiency. In pediatrics, postpyloric enteral feeding is increasingly utilized to overcome problems related to aspiration, severe reflux, poor gastric motility, and gastric outlet obstruction. However, little is known about the prevalence of copper deficiency in this population. We describe three pediatric patients receiving exclusive jejunal feeds who developed cytopenias secondary to copper deficiency.
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http://dx.doi.org/10.1002/pbc.26617DOI Listing
November 2017

Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Clin Cancer Res 2017 Jul 20;23(14):3649-3656. Epub 2017 Jan 20.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531. There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measured by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with /WT, /ITD, or /ALM ( = 0.25). High cell-surface CD135 expression was associated with FAB M5 subtype ( < 0.001), rearrangements ( = 0.009), and inversely associated with inv(16)/t(16;16) ( < 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression. FLT3 cell-surface expression did not vary by mutational status, but high FLT3 expression was strongly associated with rearrangements. Our study found that there was no prognostic significance of FLT3 cell surface expression in pediatric AML. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511553PMC
July 2017

Pseudothrombocytopenia due to Platelet Clumping: A Case Report and Brief Review of the Literature.

Case Rep Hematol 2016 4;2016:3036476. Epub 2016 Dec 4.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Platelet clumping is a common laboratory phenomenon that complicates or precludes reporting of platelet count. It is often, but not always, a phenomenon commonly caused by the anticoagulant EDTA. Herein, we discuss a case of a 14-year-old girl who was found to have platelet clumping and discuss the work-up she underwent to investigate her pseudothrombocytopenia.
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http://dx.doi.org/10.1155/2016/3036476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164902PMC
December 2016

Pediatric Oral/Maxillofacial Soft Tissue Sarcomas: A Clinicopathologic Report of Four Cases.

Case Rep Oncol 2016 May-Aug;9(2):447-453. Epub 2016 Aug 17.

Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, Ohio, USA; Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.

Pediatric soft tissue sarcomas of the oral/maxillofacial region are rare neoplasms that present significant difficulty with respect to treatment and local control measures. We report four cases of pediatric oral/maxillofacial soft tissue sarcomas from our tertiary care pediatric hospital and emphasize the rarity of these malignancies and the challenges encountered in treating these lesions, and suggest areas for further research. We conclude that multimodal therapy and interdisciplinary cooperation are paramount to successful management of these lesions.
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http://dx.doi.org/10.1159/000447689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043172PMC
August 2016

Thrombocytopenia Pitfalls: Misdiagnosing Type 2B von Willebrand Disease as Ethylenediaminetetraacetic Acid-Dependent Pseudothrombocytopenia.

J Pediatr 2016 Aug 20;175:238-238.e1. Epub 2016 May 20.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.

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http://dx.doi.org/10.1016/j.jpeds.2016.04.077DOI Listing
August 2016

Aberrant "Barbed-Wire" Nuclear Projections of Neutrophils in Trisomy 18 (Edwards Syndrome).

Case Rep Hematol 2015 8;2015:163857. Epub 2015 Dec 8.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

We discuss the significance of neutrophils with increased, aberrant nuclear projections mimicking "barbed-wire" in a newborn child with trisomy 18 (T18). Increased, aberrant nuclear projections have been previously reported in trisomy of the D group of chromosomes (chromosomes 13, 14, and 15), and we report similar findings in a patient with T18. The peripheral blood smear showed relative neutrophilia with the majority (37%) of neutrophils showing two or more thin, rod-shaped or spike-shaped, and often pedunculated aberrant nuclear projections. The number of projections ranged from 2 to 6 per cell, averaged 2 per affected neutrophil, and ranged in length from 0.22 μm to 0.83 μm. This case confirms that the morphologic finding described is not restricted to trisomy of one of the chromosomes in group D, as implied in the literature.
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http://dx.doi.org/10.1155/2015/163857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684843PMC
January 2016

Promyelocytic Leukemia with No Retinoic Acid Receptor Alpha Abnormality but with RUNX1T1 Insertion to Chromosome 7q: A Classification and Management Dilemma.

Case Rep Hematol 2015 17;2015:412016. Epub 2015 Aug 17.

Department of Pathology, The Ohio State University, Columbus, OH 43210, USA ; Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

A case of acute promyelocytic leukemia (APL) with RUNX1T1 insertion to 7q is described and compared to reported cases of APL with negative retinoic acid receptor alpha (RARA) abnormality. In this report, we describe the case of a 2-year-old boy who presented with bone pain and was found to have pancytopenia. Bone marrow examination showed morphologic and immunophenotypic findings typical of APL, but conventional cytogenetics, fluorescence in situ hybridization (FISH), and real-time polymerase chain reaction (RT-PCR) showed no evidence of RARA rearrangements. The only cytogenetic abnormality found was a small insertion in 7q, and three copies of RUNX1T1. Gene sequencing results became available after initiating therapy but were not informative. We describe the rarity of such cases and discuss how the typical morphologic and immunophenotypic findings of APL, coupled with the definite absence of RARA rearrangement (by FISH and RT-PCR), present a diagnostic and classification dilemma, raising the possibility of an unknown alternative mechanism for the leukemogenesis and maturation arrest seen in other APL variants. The diagnostic challenges and urgent management issues this unusual case raises may justify including it, along with similar cases, in a separate subtype of acute myeloid leukemia (AML) in future classifications.
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http://dx.doi.org/10.1155/2015/412016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4553303PMC
September 2015

The College of American Pathologists guidelines for whole slide imaging validation are feasible for pediatric pathology: a pediatric pathology practice experience.

Pediatr Dev Pathol 2015 Mar-Apr;18(2):109-16. Epub 2014 Nov 11.

1 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

Whole slide imaging (WSI) is rapidly transforming educational and diagnostic pathology services. Recently, the College of American Pathologists Pathology and Laboratory Quality Center (CAP-PLQC) published recommended guidelines for validating diagnostic WSI. We prospectively evaluated the guidelines to determine their utility in validating pediatric surgical pathology and cytopathology specimens. Our validation included varied pediatric specimen types, including complex or less common diagnoses, in accordance with the guidelines. We completed WSI review of 60 surgical pathology cases and attempted WSI review of 21 cytopathology cases. For surgical pathology cases, WSI diagnoses were highly concordant with glass slide diagnoses; a discordant diagnosis was observed in 1 of 60 cases (98.3% concordance). We found that nucleated red blood cells and eosinophilic granular bodies represented specific challenges to WSI review of pediatric specimens. Cytology specimens were more frequently discordant or failed for technical reasons, with overall concordance of 66.7%. Review of pediatric cytopathology specimens will likely require image capture in multiple focal planes. This study is the first to specifically evaluate WSI review for pediatric specimens and demonstrates that specimens representing the spectrum of pediatric surgical pathology practice can be reviewed using WSI. Our application of the proposed CAP-PLQC guidelines to pediatric surgical pathology specimens is, to our knowledge, the first prospective implementation of the CAP-PLQC guidelines.
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http://dx.doi.org/10.2350/14-07-1523-OA.1DOI Listing
May 2015

Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531.

J Clin Oncol 2014 Sep;32(27):3021-32

Purpose: To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.

Patients And Methods: Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).

Results: There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).

Conclusion: GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.
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http://dx.doi.org/10.1200/JCO.2014.55.3628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498PMC
September 2014

Phagocytized neutrophil fragments in the bone marrow: a phenomenon most commonly associated with hodgkin lymphoma.

ISRN Hematol 2014 18;2014:363854. Epub 2014 Mar 18.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.

Bone marrow macrophages containing other cells, or large pieces of other cells, represent a distinctive feature of diseases such as Hemophagocytic Lymphohistiocytosis (HLH) and Rosai-Dorfman disease. We describe a distinct variation of phagocytic histiocyte morphology, featuring histiocytes containing predominantly fragments of neutrophil nuclei. We retrospectively reviewed initial bone marrow samples for Hodgkin lymphoma, Burkitt lymphoma, Ewing sarcoma, or evaluation for nonneoplastic conditions, scoring the presence or absence of the above-described histiocytes. We find that these histiocytes, which we term "fragmentophages," are associated with staging marrow sampling for malignancy, especially Hodgkin lymphoma (Hodgkin lymphoma: 28/34 or 82.4%, Ewing sarcoma: 11/26 or 42.3%, Burkitt lymphoma: 4/13 or 30.8%). These cells are significantly less common in marrow samples for nonneoplastic conditions (4/21 or 19.0%). Fragmentophages are significantly associated with malignancy, especially Hodgkin lymphoma, and their recognition has the potential to provide a clue to an underlying malignancy.
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http://dx.doi.org/10.1155/2014/363854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976940PMC
July 2014

Secondary Acute Myeloid Leukemia in a One-Year-Old Girl Diagnosed with JAK2-V617F Mutation Positive Myeloproliferative Neoplasm.

Case Rep Med 2014 18;2014:473297. Epub 2014 Mar 18.

Department of Hematology/Oncology/BMT, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.
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http://dx.doi.org/10.1155/2014/473297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976921PMC
April 2014

Xanthogranulomatous appendicitis in a child: report of a case and review of the literature.

Case Rep Med 2013 4;2013:498191. Epub 2013 Sep 4.

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.

Xanthogranulomatous inflammation is a well-described inflammatory process, which may involve any organ but is most frequently encountered in the gall bladder and the kidney. There are rare reports of xanthogranulomatous appendicitis (XA) in the adult population, but only one brief mention of such a diagnosis in a child. In this report, we describe the case of an 11-year-old boy who presented with clinical signs and symptoms of acute appendicitis necessitating appendectomy. Upon microscopic examination, the appendix showed the typical features of XA. To the best of our knowledge, this is the first well-described case XA in a noninterval appendix in a child. We also reviewed the limited medical literature on the subject.
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http://dx.doi.org/10.1155/2013/498191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777195PMC
October 2013

Platelet hyperreactivity: report of a case with catastrophic arterial thrombosis in a child.

Lab Hematol 2012 Dec;18(4):22-6

Department of Pathology, The Ohio State University, Columbus, OH, USA.

Platelet hyperreactivity is an important but under-recognized cause of idiopathic arterial thrombosis. We describe a case of arterial thrombosis in a previously healthy 12-year-old girl after minor trauma to the knee, resulting in lower extremity amputation. Family history was positive for arterial and venous thrombosis, but an extensive work-up for the usual inherited thrombophilia risk factors was negative. The patient was eventually diagnosed with platelet hyperreactivity and remains on life-long antiplatelet therapy.Consideration of platelet hyperreactivity in the evaluation of unusual arterial thrombotic events allows for targeted therapy, potential avoidance of future events, and timely screening of family members.
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http://dx.doi.org/10.1532/LH96.12006DOI Listing
December 2012

Burkitt's leukemia with an atypical immunophenotype: report of a case and review of literature.

Lab Hematol 2011 Dec;17(4):27-31

Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.

Burkitt's leukemia (BL) constitutes a small but important fraction of acute leukemias in children. It is an aggressive type of leukemia that is responsive to high-intensity, short-duration chemotherapy with complete remission possible in 75% to 90% of cases. The recognition and proper designation of BL is important because treatment differs from that of precursor B-cell acute lymphoblastic leukemia (pre-B ALL). Burkitt's leukemia is separated by its typical morphologic features (blasts with typical French-American-British [FAB] L-3 morphology compared to FAB L-1/L-2 morphology in pre-B ALL) and a classic immunophenotype (blast positivity for CD45 [bright], CD20 [bright], CD10, CD19, surface immunoglobulin [SIg], Ig light chain restriction, and negative terminal deoxynucleotidyl transferase [TdT]) compared to pre-B ALL blasts (which are positive for CD45 [dim], CD10, CD19, and TdT and negative for CD20 and SIg). The diagnosis of Burkitt's leukemia is confirmed by the characteristic cytogenetic findings.The combination of Burkitt's morphology with precursor B-cell immunophenotype may present a diagnostic pitfall, resulting in delay of proper management.We describe such an atypical case in a 12-year-old girl and emphasize that correct classification and treatment starts with proper morphologic/immunophenotypic correlation, and the awareness of the overlapping features in some cases.
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http://dx.doi.org/10.1532/LH96.11004DOI Listing
December 2011

Role of methylenetetrahydrofolate reductase gene (MTHFR) 677C>T polymorphism in pediatric cerebrovascular disorders.

J Child Neurol 2011 Mar 26;26(3):318-21. Epub 2011 Jan 26.

Division of Child Neurology, The Ohio State University, Columbus, Nationwide Children's Hospital, OH 43205, USA.

Homozygosity for the methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation (MTHFR TT) has been linked to an increased risk for stroke, coronary artery disease, and migraine headaches. The authors analyzed the potential link between MTHFR 677C>T homozygosity and childhood stroke. A true association might facilitate screening, recurrence risk stratification, and treatment in patients with cerebrovascular disease. They performed a retrospective chart review of children tested for the MTHFR 677C>/T mutation; 533 patients underwent MTHFR testing, and 8% were homozygous for the MTHFR 677C>T mutation. There was no difference in the cohort compared with the prevalence in the general population. This suggests that the MTHFR 677 C>T polymorphism played a minimal role or no role in stroke risk. However, the data suggest that the MTHFR TT genotype may influence migraine susceptibility in children because there was a higher proportion of migraine patients (28.6%) with the MTHFR TT homozygous genotype.
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http://dx.doi.org/10.1177/0883073810381446DOI Listing
March 2011