Publications by authors named "Joseph R Stanek"

31 Publications

COVID-19 in immunocompromised patients: A systematic review of cancer, hematopoietic cell and solid organ transplant patients.

J Infect 2021 Feb 4. Epub 2021 Feb 4.

Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205 United States; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH, United States; Division of Infectious Diseases, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205 United States; The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.

Background: The clinical impact of severe coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in immunocompromised patients has not been systematically evaluated.

Methods: We reviewed current literature reporting on COVID-19 in cancer (CA), hematopoietic cell (HCT), and solid organ transplant (SOT) patients and compared their clinical data and outcomes to the general population. For adult CA, HCT and SOT patients, an extensive search strategy retrieved all articles published until July 20, 2020 by combining the terms coronavirus, coronavirus infection, COVID-19, and SARS-CoV-2 in PubMed, Cochrane, and Web of Science, and following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. For the pediatric CA cohort, a global COVID-19 registry was used. For the general population cohort, a large meta-analysis was used to compare pooled prevalence estimates, and two large meta-analyses were utilized to serve as pooled comparators for hospitalized COVID-19 patients.

Findings: Compared to the general population, adult CA and SOT patients with COVID-19 had higher comorbidities, greater levels of inflammatory markers at diagnosis, and higher rates of intensive care and hospital mortality. Pediatric CA patients and HCT patients with COVID-19 tended to have clinical presentations and outcomes similar to the general population.

Interpretation: To our knowledge, this is the first systematic review evaluating COVID-19 phenotype and outcomes in immunocompromised patients and comparing them to the general population, which shows that hospital outcomes appear to be worse in adult CA and SOT patients, potentially due to their higher co-morbidity burden.

Funding: None.
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http://dx.doi.org/10.1016/j.jinf.2021.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859698PMC
February 2021

Pediatric Osteopathic Manipulative Medicine: A Scoping Review.

Pediatrics 2021 Feb;147(2)

Department of Hematology/Oncology/BMT, Riley Hospital for Children, Indianapolis, Indiana.

Context: A common reproach precluding the use of osteopathic manipulative medicine (OMM) in pediatrics is a lack of evidence regarding its safety, feasibility, and effectiveness.

Objective: We conducted a systematic, scoping review of pediatric osteopathic medicine to identify gaps in the literature and make recommendations for future research.

Data Sources: We searched 10 databases using 6 key words and medical subject heading terms for any primary articles reporting OMM use in children published from database inception until initiation of the study.

Study Selection: Articles were selected if they reported primary data on OMM conducted in the United States on patient(s) 0 to 18 years old.

Data Extraction: Baseline study characteristics were collected from each article and the Grading of Recommendations, Assessment, Development, and Evaluations system was used to critically appraise each study.

Results: Database search yielded 315 unique articles with 30 studies fulfilling inclusion and exclusion criteria. Of these, 13 reported the data required to demonstrate statistically significant results, and no significant adverse events were reported. The majority of studies were graded as providing weak clinical evidence because of significant methodologic flaws and biases.

Limitations: The review was limited to US-based studies and reports. Minimal discrepancies between reviewers were resolved via an objective third reviewer.

Conclusions: There is little strong, scientific, evidence-based literature demonstrating the therapeutic benefit of OMM for pediatric care. No strong clinical recommendations can be made, but it can be medically tolerated given its low risk profile. High-quality, scientifically rigorous OMM research is required to evaluate safety, feasibility, and efficacy in pediatrics.
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http://dx.doi.org/10.1542/peds.2020-016162DOI Listing
February 2021

A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders.

Transfusion 2021 Jan 21. Epub 2021 Jan 21.

Division of Hematology, Oncology, Blood and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio, USA.

Background: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent.

Study Design And Methods: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 10 /kg) (Group B2) following failed SM and first apheresis attempts.

Results: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted.

Conclusion: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.
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http://dx.doi.org/10.1111/trf.16260DOI Listing
January 2021

Venous thromboembolism in children with central nervous system tumors: Comparison of an institutional cohort to a national administrative database.

Pediatr Blood Cancer 2021 Mar 19;68(3):e28846. Epub 2020 Dec 19.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population.

Procedure: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database.

Results: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort.

Conclusions: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.
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http://dx.doi.org/10.1002/pbc.28846DOI Listing
March 2021

Costs of Cord Blood Transplantation Are Higher Than Other Graft Sources in Patients with Acute Leukemia and Myelodysplastic Syndrome Treated at Pediatric Centers.

Biol Blood Marrow Transplant 2020 12 19;26(12):e313-e315. Epub 2020 Sep 19.

Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio.

In this commentary, we discuss the reasons why umbilical cord blood (UCB) allogeneic stem cell transplants are more expensive than matched related and matched unrelated peripheral blood and bone marrow transplants in patients treated at pediatric centers. We compare results of our previously published study with the recently published study from the Center for International Bone Marrow Transplant and Research/Pediatric Health Information System and also highlight the factors that contribute to increased costs of UCB transplants.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.011DOI Listing
December 2020

Prevalence and management of constipation in pediatric acute lymphoblastic leukemia in U.S. children's hospitals.

Pediatr Blood Cancer 2020 11 7;67(11):e28659. Epub 2020 Sep 7.

Division of Hematology/Oncology, Nationwide Children's Hospital, Columbus, Ohio.

Background: Children with acute lymphoblastic leukemia (ALL) suffer from a litany of chemotherapy-induced side effects. Constipation secondary to vinca alkaloids, environmental changes, and opioid use is a common issue for children newly diagnosed with leukemia.

Procedure: We analyzed data from 48 children's hospitals in the Pediatric Health Information System, extracting patients 1-21 years of age with ALL hospitalized from October 2015 through September 2019. Our objective was to investigate the prevalence, risk factors, and treatment of constipation in hospitalized children with ALL.

Results: We identified 4647 unique patients with an ALL induction admission. Constipation was the most common gastrointestinal diagnosis with 1576 (33.9%; 95% confidence interval [CI]: 32.6%-35.3%) patients diagnosed during induction admission and 19.8% in post-induction admissions. The most commonly administered constipation medications were poly-ethyl glycol (n = 3385, 89.6%), followed by senna (n = 1240, 32.8%), lactulose (n = 916, 24.2%), and docusate (n = 914, 24.2%). Multivariate logistic regression revealed the following variables to be significantly associated with the presence of a constipation diagnosis: age < 6 years at induction (compared with those ≥12 years; odds ratios [OR] = 1.32 [95% CI: 1.13-1.55]; P = < 0.001), female sex (OR = 1.16 [95% CI: 1.02-1.31]; P = 0.024), increased length of hospitalization (OR = 1.03 [95% CI: 1.02-1.04]; P < 0.0001), use of non-fentanyl opioids for one or two days (OR = 1.28 [95% CI: 0.99-1.65]; P = 0.056), and use of non-fentanyl opioids > 2 days (OR = 1.53 [95% CI: 1.19-1.95]; P < 0.001).

Conclusions: A large portion of hospitalized children with ALL experience constipation and required medications. Increased attention should be paid to constipation prophylaxis and treatment in ALL patients, particularly at the start of induction therapy.
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http://dx.doi.org/10.1002/pbc.28659DOI Listing
November 2020

Improving Occupational Performance in Pediatric Hematopoietic Cell Transplant Recipients.

Am J Occup Ther 2020 Sep/Oct;74(5):7405205020p1-7405205020p11

Jeffery J. Auletta, MD, is Director, Blood and Marrow Transplant Program, Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus OH; Director, Host Defense Program, Infectious Diseases, Nationwide Children's Hospital, Columbus, OH; and Member, Leukemia Research Program, The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Importance: There is a critical gap in the literature regarding the efficacy of occupational therapy interventions for pediatric hematopoietic cell transplantation (HCT) patients.

Objective: To demonstrate that occupational therapy 4-5×/wk during inpatient hospitalization positively affects strength, coordination, and independence in activities of daily living (ADLs) of pediatric patients during HCT.

Design: Retrospective study.

Setting: Inpatient bone marrow transplant unit at a children's hospital.

Participants: Thirty-two pediatric patients admitted for HCT.

Outcomes And Measures: Patients were seen by an occupational therapist as part of an interdisciplinary program. Interventions included play and leisure engagement, upper extremity therapeutic exercises, fine motor activities, and ADL training. Strength, coordination, and daily living skills data were documented prospectively and analyzed retrospectively to compare differences between patients seen by occupational therapy at high versus low frequency.

Results: For grip strength (dynamometer), fine motor dexterity (the 9-Hole Peg Test), and independence in ADLs (an ADL functional measure and the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test Daily Activities), the high-frequency group had a significantly smaller decrease in performance from time of admission at pretransplant (baseline) to peak decline after transplant. Grip strength and ADL scores for the high-frequency group returned to baseline at time of discharge more readily than for the low-frequency group.

Conclusions And Relevance: Participation in occupational therapy 4-5×/wk had positive effects on strength, coordination, and independence in ADLs for patients undergoing HCT.

What This Article Adds: This article provides evidence that occupational therapists are an important part of the interdisciplinary team treating pediatric bone marrow transplant patients. It also demonstrates that occupational therapy interventions delivered at a high frequency can have a positive impact on upper extremity strength and independence in ADLs.
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http://dx.doi.org/10.5014/ajot.2020.040543DOI Listing
September 2020

Trends in Anemia, Iron, Therapy, and Transfusion in Hospitalized Pediatric Patients with Inflammatory Bowel Disease.

J Pediatr 2020 07 20;222:141-145.e1. Epub 2020 May 20.

Division of Pediatric Hematology/Oncology, Nationwide Children's Hospital/The Ohio State University, Columbus, OH; Center for Innovation in Pediatric Practice, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH. Electronic address:

Objective: To evaluate trends in diagnosis and management of iron deficiency anemia using a large national children's hospital database in pediatric patients admitted with inflammatory bowel disease (IBD).

Study Design: In this retrospective multicenter cohort study, we used the Pediatric Health Information System de-identified administrative database. Patients age <21 years with ≥2 admissions with International Classification of Disease, Ninth Revision and Tenth Revision codes for Crohn's disease or ulcerative colitis from 2012 to 2018 were included. We extracted data regarding diagnoses of anemia and/or iron deficiency, and receipt of oral iron, intravenous (IV) iron, and/or blood transfusion. Data were analyzed descriptively.

Results: We identified 8007 unique patients meeting study criteria for a total of 28 260 admissions. The median age at admission was 15.4 years. A diagnosis of anemia was documented in 29.8% of admissions and iron studies were performed in 12.6%. IV iron was given in 6.3% of admissions and blood transfusions in 7.4%. The prevalence of the diagnosis of anemia among IBD admissions increased from 24.6% in 2012 to 32.4% in 2018 (P < .0001). There was a steady increase in the proportion of IBD admissions that used IV iron, from 3.5% in 2012 to 10.4% in 2018 (P < .0001), and the proportion of admissions with red cell transfusions decreased over time from 9.4% to 4.4% (P < .0001).

Conclusions: Iron deficiency anemia is prevalent among pediatric patients with IBD admitted to US children's hospitals. From 2012 to 2018, there was an increase in the use of inpatient IV iron for the treatment of iron deficiency anemia and a decrease in transfusions.
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http://dx.doi.org/10.1016/j.jpeds.2020.02.071DOI Listing
July 2020

Meta-Analysis of Treatment Modalities in Metastatic Atypical Teratoid/Rhabdoid Tumors in Children.

Pediatr Neurol 2020 07 8;108:106-112. Epub 2020 May 8.

The Ohio State University College of Medicine, Columbus, Ohio; Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio. Electronic address:

Background: Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy, and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patients.

Methods: We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included through chart review of patients treated at Nationwide Children's Hospital.

Results: Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death.

Conclusions: Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.03.003DOI Listing
July 2020

Pineoblastoma in children less than six years of age: The Head Start I, II, and III experience.

Pediatr Blood Cancer 2020 06 18;67(6):e28252. Epub 2020 Mar 18.

The Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio.

Background: We report the outcomes of patients with pineoblastoma and trilateral retinoblastoma syndrome enrolled on the Head Start (HS) I-III trials.

Methods: Twenty-three children were enrolled prospectively between 1991 and 2009. Treatment included maximal surgical resection followed by five cycles of intensive chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction.

Results: Median age was 3.12 years (range, 0.44-5.72). Three patients withdrew from the study treatment and two patients experienced chemotherapy-related death. Eight patients experienced progressive disease (PD) during induction chemotherapy and did not proceed to HDCx/AuHCR. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range, 18-36 Gy) with boost(s) (median dose 27 Gy; range, 18-36 Gy); three received CSI as adjuvant therapy (two post-HDCx/AuHCR) and four upon progression/recurrence. The five-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95% confidence intervals [CI]: 2.6%-36.0%) and 13% (95% CI: 4.5%-37.5%), respectively. Only three patients survived beyond five years. Favorable OS prognostic factors were CSI (hazard ratio [HR] = 0.30 [0.11-0.86], P = 0.025) and HDCx/AuHCR (HR = 0.40 [0.16-0.99], P = 0.047).

Conclusions: Within the HS I-III trials, CSI and HDCx/AuHCR were statistically associated with improved survival. The high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles prior to consolidation and the potential intensification of consolidation with multiple cycles of marrow-ablative chemotherapy and irradiation.
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http://dx.doi.org/10.1002/pbc.28252DOI Listing
June 2020

Laboratory monitoring during pregnancy and post-partum hemorrhage in women with von Willebrand disease.

J Thromb Haemost 2020 03 22;18(3):604-608. Epub 2020 Jan 22.

Department of Biostatistics and Epidemiology, Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Background: Evidence-based guidelines recommend that von Willebrand factor (VWF) levels be obtained in the third trimester of pregnancy to facilitate peripartum planning for women with von Willebrand disease (VWD).

Objectives: To identify the frequency of third trimester monitoring in a nationally representative sample of pregnant women with VWD in the United States, as well as the frequency of reproductive bleeding after pregnancy.

Patients/methods: Patient data were obtained from the Truven Health MarketScan Research Databases. International Classification of Diseases-9 codes were used to identify women with VWD and evidence of infant delivery. We defined third trimester monitoring as a laboratory claim for VWF levels during the 3 months before delivery. Clinical outcomes studied included postpartum hemorrhage (PPH) and heavy menstrual bleeding (HMB).

Results: We identified 2238 unique pregnant females with VWD. Of these, 32% (n = 714) underwent third-trimester testing of VWF levels. Diagnostic codes consistent with PPH were recorded for 6.5% of women in the 6 weeks after infant delivery. The frequency of PPH in women who underwent VWF monitoring (4.9%) was significantly lower than in those who did not undergo monitoring (7.3%), (risk difference -2.4%, 95% CI -4.4% to -0.3%, P = .023). Diagnostic codes consistent with HMB were recorded for 4.7% of women in the 3 months after infant delivery.

Conclusions: Third-trimester VWF monitoring was associated with a lower risk of PPH, but testing was performed in only one-third of insured pregnant women with VWD in the United States despite expert recommendations.
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http://dx.doi.org/10.1111/jth.14696DOI Listing
March 2020

Renal Tumors in Children and Young Adults Older Than 5 Years of Age.

J Pediatr Hematol Oncol 2020 05;42(4):287-291

Surgery, Division of Pediatric Surgery, The Ohio State University College of Medicine and Nationwide Children's Hospital, Columbus, OH.

Renal masses are most common in children between ages 1 to 3 years, with less known about renal tumors in older children and young adults. The aim of this study was to review the presentation, demographics, histology, and outcomes in patients over 5 years of age with renal tumors compared with younger children. 111 renal tumors were diagnosed in patients 5 years of age and older (median, 7 y; range, 5 to 31 y) between 1950 and 2017 at a single institution. Wilms tumor (WT) was the most common histology in 84 patients (75%), followed by renal cell carcinoma in 12 patients (10.7%). Abdominal pain was the most common presenting symptom (46%) followed by hematuria (28.8%), and a palpable abdominal mass (24.3%). For WT, older children more commonly presented with advanced-stage disease (stages 3 and 4) than younger children (57.7% vs. 11.5%; P<0.001). Event-free survival (EFS) and overall survival (OS) for favorable histology WT were not different between younger and older children (OS, P=0.43; EFS, P=0.46). In this cohort, older children more frequently present with variable signs and symptoms, less common histopathologies although WT was still most frequent, and more advanced-stage disease compared with younger cohorts, but without differences in EFS or OS.
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http://dx.doi.org/10.1097/MPH.0000000000001593DOI Listing
May 2020

Allocation of Treatment Responsibility and Adherence to Hydroxyurea Among Adolescents With Sickle Cell Disease.

J Pediatr Psychol 2019 11;44(10):1196-1204

Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center.

Objective: Adolescents with sickle cell disease (SCD) are at increased risk for complications. Hydroxyurea is a medication that can ameliorate risk but to benefit, adolescents must adhere to treatment. Study aims were to describe how adolescents and their caregivers decided who was responsible for treatment tasks, to describe adolescents' and caregivers' responsibility for these tasks, and to examine if hydroxyurea adherence was associated with younger adolescent age, less discrepancy between adolescents' and caregivers' reports of adolescent responsibility, and higher caregiver involvement.

Methods: Twenty-nine dyads completed treatment responsibility measures. A combination of laboratory and electronic prescription data were used to determine hydroxyurea adherence and electronic medical records were used to determine appointment adherence.

Results: Few dyads agreed or planned how to complete treatment tasks. Adolescents shared responsibility with caregivers for medication-taking tasks. Adolescents perceived caregivers and caregivers perceived adolescents were overall responsible for treatment, especially for appointment tasks. Half of adolescents were adherent to hydroxyurea and half were adherent to appointments but medication adherence was not associated with age, discrepancy between adolescents' and caregivers' responses, or caregiver involvement.

Conclusions: Despite frequent hydroxyurea and appointment nonadherence, few adolescents and caregivers plan how to manage adolescents' SCD treatment or perceive they are overall responsible. Future studies are needed to determine the factors that influence these perceptions and if increasing adolescent and caregiver treatment planning improves adherence and clinical outcomes.
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http://dx.doi.org/10.1093/jpepsy/jsz061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823103PMC
November 2019

Delays in diagnosis for children with newly diagnosed central nervous system tumors.

Neurooncol Pract 2018 Nov 9;5(4):227-233. Epub 2018 Mar 9.

The Division of Hematology, Oncology and BMT, Nationwide Children's Hospital, Columbus, Ohio.

Background: United States studies documenting time interval from symptom onset to definitive diagnosis for childhood central nervous system (CNS) tumors are more than a quarter-century old. The purpose of this study is to establish an accurate and contemporary Ohio baseline of the diagnostic interval for children with newly diagnosed CNS tumors.

Methods: Medical records were retrospectively reviewed for 301 children with newly diagnosed CNS tumors from January 2004 to August 2015 at Nationwide Children's Hospital. We obtained comprehensive data on 171 patients (56.8%). Records were reviewed for age, gender, tumor type, presenting symptoms, number of health care visits prior to diagnosis, time interval (in months) from onset of symptoms to definitive diagnosis, and any associated genetic syndromes.

Results: Of the 171 patients with newly diagnosed CNS tumors, 25 children (14.6%) had a known cancer predisposition syndrome (all with neurofibromatosis type 1). Among the remaining 146 children, the median and mean time intervals from symptom onset to definitive diagnosis were 42 days and 138 days (range < 1 to 2190 days), respectively.

Conclusions: We have documented and quantified the contemporary delays in diagnosis of childhood brain tumors in central Ohio to serve as a benchmark for our future planned interventions to reduce the time interval from symptom onset to diagnosis through adaptation of the United Kingdom HeadSmart program throughout the state of Ohio and ultimately throughout the United States.
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http://dx.doi.org/10.1093/nop/npy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655489PMC
November 2018

Screening urinalysis demonstrates that haematuria is a frequent finding in persons with haemophilia treated at a paediatric haemophilia treatment centre.

Haemophilia 2019 Sep 10;25(5):782-788. Epub 2019 Jul 10.

Nationwide Children's Hospital, Columbus, Ohio.

Introduction: Haematuria is a recognized complication of haemophilia A and B (HA, HB). Adult persons with haemophilia (PWH) have a higher prevalence of renal disease than the general population. There is limited literature investigating the prevalence of haematuria in paediatric PWH.

Aim: Our paediatric haemophilia treatment centre (HTC) had previously used quality improvement methods to increase the frequency of screening urinalyses at annual comprehensive visits. We retrospectively reviewed the data collected to determine the prevalence of haematuria and explore for associations in those with haematuria.

Methods: Retrospective chart review to identify the frequency of haematuria on screening urinalysis in all male PWH ≥2 years old. Haematuria was defined as ≥3 red blood cells (RBCs) per high power field. Univariate logistic regression was performed to evaluate for associations with haematuria.

Results: A total of 93 patients met eligibility criteria. Sixty-seven with HA (11 mild, 17 moderate, 39 severe) and 26 with HB (three mild, 16 moderate, seven severe). Forty-two of ninety-three (45%) patients were identified as having haematuria (median RBCs 7, mean RBCs 332). Of those with haematuria, 76% were identified by screening UA, as opposed to clinical symptoms, and 52% had recurrent haematuria. Older age and HA were associated with an increased likelihood of haematuria.

Conclusions: Our study demonstrated that the prevalence of haematuria was high in PWH treated at our paediatric HTC. Future investigation is needed to determine the population-wide prevalence of haematuria in paediatric PWH and its impact on renal function.
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http://dx.doi.org/10.1111/hae.13815DOI Listing
September 2019

The Risk of Developing Secondary Central Nervous System Tumors After Diagnostic Irradiation From Computed Tomography in Pediatrics: A Literature Review.

Pediatr Neurol 2019 09 5;98:18-24. Epub 2019 Apr 5.

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

Background: Advanced diagnostic imaging has provided tremendous benefits; however, increased use of ionizing radiation modalities such as cranial computed tomography (CT) may be associated with an increased risk of developing central nervous system tumors.

Methods: A literature review identified studies published for more than the last 50 years from 1968 to 2018 that explored the association between head CT scans and developing central nervous system tumors in pediatrics. We reviewed seven studies that described and analyzed the risk of brain tumors.

Results: A positive correlation between exposure to CT scans and developing central nervous system tumors was evident in all cohorts. The strength of the association varied across the studies. Exclusion of patients with predisposing factors to central nervous system tumors was examined in four studies with a decreased risk to develop central nervous system tumors noted in three studies. Two studies reported nonsignificant reduction in the excess relative risk per milliGray of brain dose after adjusting for predisposing factors, whereas the reduction was significant in one study. The frequency of CT exposure was proportional to the risk of developing tumors in two studies although not significantly maintained in two other studies. Gender had no significant effect on the central nervous system tumor risk. The calendar year at the time of imaging showed decreasing risk in those exposed to CT in more recent years compared with prior decades.

Conclusions: Prospective epidemiologic studies are needed to examine the precise carcinogenic effect of exposure to ionizing radiation and help tailor further preventive measures.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.03.028DOI Listing
September 2019

Transplant Energize Me Patient Outcome (TEMPO): A Quality Improvement Project that Maintains Functional Mobility in Pediatric Patients Admitted for Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 11;25(9):1779-1785. Epub 2019 May 11.

Hematology/Oncology/Blood and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio; Host Defense Program, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Allogeneic hematopoietic cell transplantation (HCT) remains the definite cure for many pediatric hematologic diseases but causes profound deconditioning, which impairs daily physical functioning and may lead to further health complications. The Transplant Energize Me Patient Outcome (TEMPO) project is a standard-of-care, quality improvement (QI) project whose primary objective is to maintain physical functional mobility and strength throughout admission for pediatric allogeneic HCT patients. Specifically, TEMPO incorporates individualized and developmentally appropriate exercises and activities that are administered by a multidisciplinary team, who objectively measure and record a patient's physical stamina at predetermined frequencies. Discipline-specific metrics at admission, at weekly intervals, at discharge, and at 100 days after graft infusion (D100) are recorded in templated flowsheets in the electronic medical record. As a secondary objective, resource utilization as measured by length of stay, duration of parenteral feeds and narcotics, readmission by D100, and infections was compared between TEMPO and historical control (pre-TEMPO) allogeneic HCT patients. TEMPO participation maintained physical endurance and functional strength throughout hospitalization, an effect that was significantly sustained or improved at D100. Resource utilization did not significantly differ between patient cohorts. Taken together, the TEMPO QI Project maintains physical functional mobility, strength, and endurance, thereby decreasing physical deconditioning in pediatric allogeneic HCT patients, an effect that is objectively sustained at D100.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.004DOI Listing
September 2019

Anti-Factor Xa-Based Monitoring of Unfractionated Heparin: Clinical Outcomes in a Pediatric Cohort.

J Pediatr 2019 06 5;209:212-219.e1. Epub 2019 Apr 5.

Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH. Electronic address:

Objectives: To assess clinical outcomes in children treated with unfractionated heparin and monitored using an anti-factor Xa (Anti-FXa)-based nomogram. We also sought to assess the correlation between activated partial thromboplastin time (APTT) and Anti-FXa.

Study Design: This was a single-center, observational cohort study conducted over a 20-month period that included all pediatric patients (<21 years) who received therapeutic unfractionated heparin and were monitored using an anti-FXa-based nomogram.

Results: In total, 95 patients met prespecified inclusion criteria, and 1098 pairs of APTT and Anti-FXa measurements were performed. The median unfractionated heparin dose required to reach therapeutic Anti-FXa goal was significantly greater in infants compared with older children (P <.0001). The median time to achieve therapeutic Anti-FXa was 10 hours (range 2-96 hours) and was significantly shorter in patients who received a bolus compared with those who did not (P = .03). Five (5.3%) major bleeding events were noted. Age, peak Anti-FXa, peak APTT, lowest platelet count, and fibrinogen were not predictive of major and clinically relevant nonmajor bleeds. Moderate correlation between the APTT and Anti-FXa (r = 0.75; 95% CI 0.72-0.77) assays was appreciated.

Conclusions: Using an anti-FXa-based nomogram to monitor unfractionated heparin in children is feasible. Although moderate correlation was observed between the APTT and Anti-FXa assays, the APTT frequently overestimated heparin activity. Safety and efficacy of an Anti-FXa nomogram needs further validation.
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http://dx.doi.org/10.1016/j.jpeds.2019.02.015DOI Listing
June 2019

A Novel Clinician-Orchestrated Virtual Reality Platform for Distraction During Pediatric Intravenous Procedures in Children With Hemophilia: Randomized Controlled Trial.

JMIR Serious Games 2019 Jan 9;7(1):e10902. Epub 2019 Jan 9.

The Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.

Background: Needles are frequently required for routine medical procedures. Children with severe hemophilia require intensive intravenous (IV) therapy to treat and prevent life-threatening bleeding and undergo hundreds of IV procedures. Fear of needle-related procedures may lead to avoidance of future health care and poor clinical outcomes. Virtual reality (VR) is a promising distraction technique during procedures, but barriers to commercially available VR platforms for pediatric health care purposes have prevented widespread use.

Objective: We hypothesized that we could create a VR platform that would be used for pediatric hemophilia care, allow clinician orchestration, and be safe and feasible to use for distraction during IV procedures performed as part of complex health care.

Methods: We created a VR platform comprising wireless, adjustable, disposable headsets and a suite of remotely orchestrated VR games. The platform was customized for a pediatric hemophilia population that required hands-free navigation to allow access to a child's hands or arms for procedures. A hemophilia nurse observing the procedure performed orchestration. The primary endpoint of the trial was safety. Preliminary feasibility and usability of the platform were assessed in a single-center, randomized clinical trial from June to December 2016. Participants were children with hemophilia aged 6-18 years. After obtaining informed consent, 25 patients were enrolled and randomized. Each subject, 1 caregiver, and 1 hemophilia nurse orchestrator assessed the degree of preprocedural nervousness or anxiety with an anchored, combined modified visual analog (VAS)/FACES scale. Each participant then underwent a timed IV procedure with either VR or standard of care (SOC) distraction. Each rater assessed the distraction methods using the VAS/FACES scale at the completion of the IV procedure, with questions targeting usability, engagement, impact on procedural anxiety, impact on procedural pain, and likability of the distraction technique. Participants, caregivers, and nurses also rated how much they would like to use VR for future procedures. To compare the length of procedure time between the groups, Mann-Whitney test was used.

Results: Of the 25 enrolled children, 24 were included in the primary analysis. No safety concerns or VR sickness occurred. The median procedure time was 10 (range 1-31) minutes in the VR group and was comparable to 9 (range 3-20) minutes in the SOC group (P=.76). Patients in both the groups reported a positive influence of distraction on procedural anxiety and pain. Overall, in 80% (34/45) of the VR evaluations, children, caregivers, and nurses reported that they would like to use VR for future procedures.

Conclusions: We demonstrated that an orchestrated, VR environment could be developed and safely used during pediatric hemophilia care for distraction during IV interventions. This platform has the potential to improve patient experience during medical procedures.

Trial Registration: Clinical Trials.gov NCT03507582; https://clinicaltrials.gov/ct2/show/NCT03507582 (Archived by WebCite at http://www.webcitation.org/73G75upA3).
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http://dx.doi.org/10.2196/10902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329423PMC
January 2019

Increased Health Care Utilization and Costs during Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and Myelodysplastic Syndromes in Adolescents and Young Adults Compared with Children: A Multicenter Study.

Biol Blood Marrow Transplant 2019 05 6;25(5):1031-1038. Epub 2019 Jan 6.

Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio.

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute leukemia and myelodysplastic syndromes (MDS) but is associated with significant cost. Compared with children (age <15 years), adolescents and young adults (AYA; age 15 to 39 years) undergoing HCT have an increased risk for transplantation-related complications. However, whether such complications translate into increased resource utilization and costs during HCT remains unknown. Therefore, we conducted a multicenter database study using the Pediatric Health Information System database, an administrative database containing resource utilization data from 49 US tertiary children's hospitals to compare inpatient costs and resource utilization in children and AYA undergoing HCT for acute leukemia and MDS. The International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients and transplantation-related complications occurring up to 1 year post-HCT. We identified 1693 HCT recipients at pediatric centers between January 2010 and September 2014. Eighty percent of the total costs (from admission for HCT up to 1 year post-HCT) occurred during the initial transplantation admission. During initial admission, although AYA and children had a similar median length of stay (LOS) of 43 days, AYA incurred significantly greater adjusted costs ($338,458 versus $275,723; P < .001) and costs per hospital day ($7122 versus $5838; P < .001). Median total costs and costs per day during subsequent time periods post-HCT were also significantly greater in the AYA group. In multivariable analysis, increasing age at HCT, LOS, use of cord blood or an unrelated donor, occurrence of any graft-versus-host disease, infection, and use of dialysis or mechanical ventilation were significant drivers of increased cost at initial admission. In conclusion, allogeneic HCT for acute leukemia and MDS is associated with higher costs in AYA recipients than in children. Therefore, directing efforts and resources aimed at reducing HCT-related costs may be advantageous in this high-risk group.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.004DOI Listing
May 2019

Technical Considerations for Nephron-Sparing Surgery in Children: What Is Needed to Preserve Renal Units?

J Surg Res 2018 12 9;232:614-620. Epub 2018 Aug 9.

Division of Pediatric Surgery, Department of Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan.

Background: Chemotherapy is used preoperatively for children with bilateral Wilms tumor (BWT) or unilateral high-risk Wilms tumor (UHRWT) to promote tumor regression to facilitate renal preservation with nephron-sparing surgery (NSS). In adults, various surgical techniques have been described to preserve renal tissue. Few studies have examined the use of surgical adjuncts in NSS in children with renal tumors.

Methods: We performed a multi-institutional retrospective review of patients with BWT or UHRWT. Patient demographics, tumor size at diagnosis, following neoadjuvant chemotherapy, utilization of surgical adjuncts including intraoperative ultrasound (IOUS), margin status, complications, renal function, and follow-up were recorded.

Results: The cohort comprised 23 patients: 18 BWT, 3 UHRWT, and 2 patients with solitary kidney. Twenty-two of the 23 patients had successful NSS. IOUS was used 19 times, and seven had positive margins after surgery. Cooling/vascular isolation was used six times. At a median follow-up of 18 mo, median estimated glomerular filtration rate Schwartz was 126 mL/min/1.73 m and median serum creatinine 0.39 mg/dL in the 22 patients who had successful NSS. There have been no tumor recurrences.

Conclusions: In patients with BWT and UHRWT, surgical adjuncts such as cooling/vascular isolation are uncommonly performed. IOUS may be helpful but does not guarantee negative microscopic margins.

Level Of Evidence: Level 4, Case series with no comparison group.
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http://dx.doi.org/10.1016/j.jss.2018.07.022DOI Listing
December 2018

The Latin American Brain Tumor Board teleconference: results of a web-based survey to evaluate participant experience utilizing this resource.

Childs Nerv Syst 2019 02 14;35(2):257-265. Epub 2018 Nov 14.

The Department of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Children's Hospital and The Ohio State University, 700 Children's Drive, Columbus, OH, 43205, USA.

Purpose: The Latin American Brain Tumor Board (LATB) is a weekly teleconference connecting pediatric neuro-oncologists from referral centers in high-income countries with pediatric subspecialists from 20 Latin American countries since 2013. This survey explored the participants' experience utilizing this resource.

Methods: A cross-sectional electronic questionnaire was distributed to 159 participants through email and Cure4Kids.

Results: Ninety-five respondents (60%) from all the participating countries completed the survey. Sixty-one reported frequent-attendance (≥ 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The most frequently reported attendance-barriers were the subspecialist's workload (64%), the timing of the teleconference (38%), and Internet connectivity problems (29%). Subspecialist's workload was more frequently reported as a barrier compared with other barriers, in both the frequent- and infrequent-attendance groups (p < 0.05), with the exception of the timing of the meeting in the infrequent-attendance group. More than 80% of attendees found the frequency and duration of the teleconference were sufficient. Utilizing Spanish as the primary language was reported to enhance the recommendations by 93% of the attendees. Moreover, 84% reported that the recommendations (almost) always fit the local circumstances. Furthermore, 99% of attendees found the teleconference provided a continuing medical education opportunity. Finally, 96% of attendees (almost) always found that the provided recommendations helped to improve the outcomes/quality of life of the patients.

Conclusions: The LATB teleconference provided a valuable tool for the management of pediatric brain tumors in Latin America as it provided a feasible and easy to access continued medical education opportunity for the participants.
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http://dx.doi.org/10.1007/s00381-018-4000-xDOI Listing
February 2019

Pediatric Histoplasmosis in an Area of Endemicity: A Contemporary Analysis.

J Pediatric Infect Dis Soc 2019 Nov;8(5):400-407

Division of Infectious Diseases and Host Defense Program.

Background: Data on pediatric histoplasmosis have been limited to those from outbreak and case reports. We sought to evaluate the contemporary clinical manifestations, laboratory findings, and outcomes in children with histoplasmosis living in an area of endemicity.

Methods: This study was a single-center retrospective review of proven and probable cases of histoplasmosis in children aged 0 to 18 years between April 2008 and April 2014. Case ascertainment was ensured by us using International Classification of Diseases, Ninth Revision codes cross-referenced with laboratory, microbiology, and histopathology tests that detected Histoplasma capsulatum. Demographics, diagnostics, clinical management, and outcomes were evaluated.

Results: Seventy-three children with histoplasmosis (41 males; median age, 13 years [range, 3-18 years]) were diagnosed with proven (n = 17 [23%]) or probable (n = 56 [77%]) histoplasmosis, which manifested as pulmonary (n = 52 [71%]) or disseminated (n = 21 [29%]) disease. Symptoms at presentation were nonspecific; the examination of 21 (29%) patients revealed abnormal physical findings. Detection of H capsulatum by serologic methods occurred in 93% (63 of 68) of the patients tested. Histoplasma antigen in blood or urine was detected in 42% (20 of 48) and 28% (15 of 53) of the patients tested, respectively. The 16 (22%) patients who were immunocompromised had significantly higher rates of disseminated disease (56% vs 21%, respectively; P = .01), antigenuria (62% vs 18%, respectively; P = .004), and antigenemia (69% vs 31%, respectively; P = .02) and longer durations of antigenuria (403 vs 120 days, respectively; P = .003) and antigenemia (451 vs 149 days, respectively; P < .0001) than did the immunocompetent children.

Conclusions: Pediatric histoplasmosis manifests most frequently as pulmonary disease. The highest diagnostic yield was achieved when multiple diagnostic modalities were used. Presentation with disseminated disease and evidence of antigenemia, antigenuria, and delayed antigen clearance were more likely to be seen in immunocompromised children.
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http://dx.doi.org/10.1093/jpids/piy073DOI Listing
November 2019

Re-induction chemotherapy regimens in patients with recurrent central nervous system mixed malignant germ cell tumors.

Childs Nerv Syst 2018 11 3;34(11):2179-2186. Epub 2018 Aug 3.

The Division of Hematology, Oncology and Blood and Marrow Transplant, Nationwide Children's Hospital, The Ohio State University, 700 Children's Dr, Columbus, OH, 43205, USA.

Background: The lack of a standard treatment approach has contributed to poor outcomes of patients with recurrent central nervous system (CNS) mixed malignant germ cell tumors (MMGCT). There are no data in the literature supporting optimal re-induction chemotherapy regimens that should be used for patients with recurrent CNS MMGCT.

Methods: We conducted a literature review to explore the response rate of patients with recurrent CNS MMGCT to different re-induction chemotherapy regimens by searching PubMed from 1985 through November 2017. Tumors were classified according to Japanese, European, and North American prognostic group classifications determined at initial presentation.

Results: Forty-two responses to various re-induction chemotherapy regimens reported in 38 patients were included. Two patients were inevaluable and their responses to re-induction chemotherapy were excluded. Thirty-five responses to various re-induction chemotherapy regimens were evaluable in 33 patients following a first relapse. Six (17%) responses were reported as complete or continuous complete responses, seven (20%) partial responses, two (6%) were stable disease, two (6%) were mixed responses, and 18 (51%) were progressive disease. Five of ten patients treated without platinum-based chemotherapy experienced tumor progression. There was a trend towards a higher rate of tumor progression among histological poor prognostic group patients, and among patients relapsing within 24 months of initial diagnosis; however, it was not statistically significant.

Conclusions: The histological prognostic group and time to relapse may affect the response to re-induction chemotherapy. However, further studies with larger sample size are needed to examine these associations and determine the optimal re-induction chemotherapy regimens for patients with recurrent MMGCT.
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http://dx.doi.org/10.1007/s00381-018-3940-5DOI Listing
November 2018

Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens.

Pediatr Blood Cancer 2018 11 17;65(11):e27313. Epub 2018 Jul 17.

Division of Hematology, Oncology, Blood and Marrow Transplant, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio.

Background: Desmoplastic small round cell tumor (DSRCT) and synovial sarcoma are rare tumors with dismal outcomes requiring new therapeutic strategies. Immunotherapies have shown promise in several cancer types, but have not been evaluated in DSRCT and synovial sarcoma. Because the immune microenvironment can provide indications of the inflammatory nature of tumors, immunohistochemical staining is able to assess the tumor immune infiltrates in both tumor types.

Procedure: Using tissue microarrays of DSRCT and synovial sarcoma tumor samples, we detected tumoral HLA-A/B/C, beta-2-microglobulin(B2M), and PD-L1 expression, and quantified tumor-infiltrating lymphocytes expressing CD4, CD8, CD56, CD45RO, or FOXP3 by immunohistochemistry. We used staining intensity on a scale of 0-3 and percentage of tumor stained to determine HLA, B2M, and PD-L1 scores. We calculated the cytotoxic T lymphocyte (CTL) target score as HLA score × B2M score/100.

Results: In diagnostic samples, we found high HLA and CTL target scores and low PD-L1 expression with decreased scores in recurrence for both tumor types. We found an increase in CD56 natural killer cells in DSRCT samples from diagnosis to recurrence.

Conclusions: We found similar immunostimulatory profiles in DSRCT and synovial sarcoma. Our findings suggest that DSRCT and synovial sarcoma may be amenable to immunotherapies, albeit there was significant heterogeneity. Interestingly, HLA and CTL target scores decreased at recurrence, possibly reflecting immunoevasion. Our findings suggest both tumor types may be amendable to CTL-based therapies at diagnosis but less so at relapse. Our results support further investigation into the prognostic and predictive value of these findings in a larger dataset.
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http://dx.doi.org/10.1002/pbc.27313DOI Listing
November 2018

Hematologic Considerations and Management of Adolescent Girls with Heavy Menstrual Bleeding and Anemia in US Children's Hospitals.

J Pediatr Adolesc Gynecol 2018 Oct 22;31(5):446-450. Epub 2018 Jun 22.

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

Study Objective: To assess the frequency, severity, and inpatient management of girls admitted with heavy menstrual bleeding and iron deficiency anemia at US children's hospitals, with a focus on hematologic considerations.

Design: Retrospective multicenter cohort study from October 2012 through September 2015.

Setting: Children's hospitals submitting data to the Pediatric Health Information System.

Participants: Female patients, age 8-18 years, admitted with heavy menstrual bleeding and anemia as either a primary or secondary diagnosis. Patients with cancer, immune thrombocytopenic purpura, aplastic anemia, and pregnancy were excluded.

Interventions And Main Outcome Measures: Hemostatic evaluation; provision of iron therapy.

Results: We identified 1183 admissions (1134 unique patients). Patients' median (interquartile range) age was 14 (11-17) years. Forty-one percent were Caucasian (n = 480), 31% African American (n = 371), and 26% Hispanic ethnicity (n = 310). Intensive care use occurred in 5% of admissions (n = 56). Hemostatic assessment was inconsistent; 15% (n = 182) had no such evaluation. Two-thirds (n = 797; 67%) involved transfusions, 37% (n = 433) received no inpatient iron therapy, and 17% (n = 197) received no hormonal or antifibrinolytic therapy. Hemostatic evaluation was associated with intensive care use: odds ratio (OR), 4.80 (95% confidence interval [CI], 1.16-19.86; P = .03); emergency department visit: OR, 2.60 (95% CI, 1.86-3.65; P < .01); private insurance: OR, 1.62 (95% CI, 1.12-2.35; P = .01); and younger age: OR, 0.84 (95% CI, 0.77-0.92; P < .01).

Conclusion: Hundreds of girls with heavy menstrual bleeding and anemia are hospitalized at US children's hospitals each year with variable inpatient hematologic evaluation and management. Future guidelines should emphasize early identification of at-risk patients and promote effective implementation strategies to reduce the burden of this preventable complication.
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http://dx.doi.org/10.1016/j.jpag.2018.06.008DOI Listing
October 2018

Venous Thromboembolism in Pediatric Hematopoietic Cell Transplant: A Multicenter Cohort Study.

Biol Blood Marrow Transplant 2018 02 8;24(2):337-342. Epub 2017 Nov 8.

Division of Pediatric Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, The Ohio State University, Columbus, Ohio.

Hematopoietic cell transplant (HCT) is associated with a proinflammatory, procoagulant environment that places recipients at increased risk of venous thromboembolism (VTE). Although the incidence of VTE in adult HCT recipients has been extensively studied, similar data for children are lacking. We conducted a multicenter retrospective study to analyze the prevalence of VTE and associated risk factors in a large cohort of patients who underwent HCT at tertiary care US children's hospitals. The Pediatric Health Information System database, a large administrative database that contains clinical and resource utilization data from 49 freestanding children's hospitals in the United States, was used to extract data. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients, VTE events, post-HCT complications, and associated risk factors up to 1 year post-transplant. Data on patients who received HCT from January 2010 through September 2014 were collected. A total of 4158 unique patients mean ± standard deviation age at transplant admit, 8.8 ± 6.5 years; range, birth to 33.4 years) were identified. After HCT 290 subjects (6.9%) developed VTE. VTE prevalence was greater in patients aged ≥ 13 versus <13 years (8.54% versus 6.33%; P = .01) and in recipients of allogeneic versus autologous grafts (7.7% versus 5%; P ≤ .01). VTE was associated with prolonged median duration of hospitalization (81 versus 54 days; P ≤.01) and increased 1-year mortality (13.9% versus 5.9%; P ≤ .01). Infections and presence of any graft-versus-host disease (GVHD) were significantly associated with VTE occurrence in recipients of allogenic grafts. Prevalence of VTE in patients who underwent HCT at pediatric tertiary care hospitals is about 7%. Age ≥ 13 years and allogeneic grafts were significant pre-HCT VTE risk factors, with GVHD and infections seen more frequently in patients with VTE.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.038DOI Listing
February 2018

VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma.

Pediatr Blood Cancer 2018 Jan 27;65(1). Epub 2017 Jul 27.

Department of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: The combination of vincristine, irinotecan, and temozolomide (VIT) is often used to treat children and adolescents with relapsed rhabdomyosarcoma (RMS); however, the outcome of these patients has not been previously described.

Procedures: We sought to determine the response rate (RR) and progression-free survival (PFS) for patients with relapsed RMS treated with VIT by retrospective review of patients treated at five tertiary care hospitals. Prior treatment with irinotecan was permitted.

Results: Among 19 patients with a median age of 8 years (range 2-17 years), 12 (63%) were males and 12 (63%) had embryonal histology. Median time to relapse from initial diagnosis was 16 months (range 2.8-45 months). VIT was used as first, second, third, or fourth line of therapy in four (21%), seven (37%), six (32%), and two (10%) patients, respectively. Four patients received VIT as adjuvant therapy following radiation and/or surgery. Therefore, among 15 evaluable patients, the best response to VIT was 0 (complete response, CR), 0 (partial response, PR), 4 (stable disease, SD), and 11 (progressive disease, PD) for an overall clinical benefit rate (CR + PR + SD) of 26.7% (95% CI: 7.8-55.1%). After a median follow-up of 8 months, 2 (10%) patients were alive without disease, 3 (16%) were alive with disease, and 14 (74%) patients died of PD. PFS at 3 months was 23% (95% CI: 5.7-46.7%).

Conclusions: VIT therapy in combination with adequate local control is associated with some disease control in patients with first relapse RMS and may be another reasonable option to offer patients as salvage therapy.
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http://dx.doi.org/10.1002/pbc.26728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497851PMC
January 2018

Cooperation of Oncolytic Herpes Virotherapy and PD-1 Blockade in Murine Rhabdomyosarcoma Models.

Sci Rep 2017 05 24;7(1):2396. Epub 2017 May 24.

Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.

Oncolytic virotherapy is an effective immunotherapeutic approach for cancer treatment via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines and promotion of antitumor T cell responses. Solid tumors limit the effectiveness of immunotherapeutics in diverse ways such as secretion of immunosuppressive cytokines and expression of immune inhibitory ligands to inhibit antitumor T cell function. Blocking programmed cell death protein (PD)-1 signaling, which mediates T cell suppression via engagement of its inhibitory ligands, PD-L1 or PD-L2, is of particular interest due to recent successes in many types of cancer. In syngeneic murine rhabdomyosarcoma models, we found that M3-9-M (MHC I high) but not 76-9 (MHC I low) tumors respond to oncolytic herpes simplex virus-1 (oHSV-1) and PD-1 blockade combination therapy. In addition, the therapeutic outcomes in M3-9-M tumor models correlated with the increased incidence of CD4 and CD8 T cells but not with the CD4CD25Foxp3 regulatory T cell populations in the tumor. Overall, our data suggest the combination of PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood soft tissue sarcoma.
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http://dx.doi.org/10.1038/s41598-017-02503-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443787PMC
May 2017

Pulmonary Nodule Size <5 mm Still Warrants Investigation in Patients With Osteosarcoma and Ewing Sarcoma.

J Pediatr Hematol Oncol 2017 04;39(3):184-187

Departments of *Surgery, Division of Pediatric Surgery †Radiology §Pediatrics, Division of Hematology, Oncology, and Bone Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University College of Medicine ‡Department of Biostatistics, The Research Institute at Nationwide Children's Hospital, Columbus, OH.

Background: Osteosarcoma (OS) and Ewing sarcoma (ES) have a high propensity to develop pulmonary metastases. Lung lesions with calcification, peripheral location, and size >5 mm are more likely to represent malignant metastases. We evaluated the incidence of malignancy in nodules 5 mm or less to potentially guide decisions between biopsy and observation.

Materials And Methods: A retrospective review of patients <25 years of age with metastatic OS and ES treated at our institution between 2001 and 2014 who had undergone pulmonary nodule biopsy was performed. Computed tomographic scans were reviewed to evaluate nodule size and change over time.

Results: Thirty-five patients (27 OS, 8 ES) met inclusion criteria. One hundred sixteen nodules were biopsied (97 OS, 19 ES). Nodule size at biopsy was not significantly different between the malignant (median, 6 mm, range, 1 to 79 mm) and benign (median, 3 mm, range, 1 to 21 mm) lesions (P=0.063). Size of pulmonary nodules <5 mm was not entirely predictive of benign status, with sensitivity estimate of 0.709 (95% confidence interval, 0.465-0.872; P=0.091) and specificity estimate of 0.776 (95% confidence interval, 0.324-0.962; P=0.219) for all nodules biopsied.

Conclusions: Pulmonary nodules in patients with OS and ES <5 mm cannot be excluded from biopsy considerations.
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http://dx.doi.org/10.1097/MPH.0000000000000753DOI Listing
April 2017