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Objective: This trial examined the effects of proximal/distal mediators and moderators of an Active Music Engagement (AME) intervention on young child/parent distress, quality of life, and family function outcomes., Methods: Child/parent dyads (n = 125) were randomized to AME or Audio-storybooks attention control condition. Each group received 3 sessions with a credentialed music therapist for 3 consecutive days with data collection at baseline, post-intervention (T2), and 30-days later (T3). Potential proximal mediators included within session child and parent engagement. Potential distal mediators included changes in perceived family normalcy, parent self-efficacy, and independent use of play materials. Potential moderators included parent/child distress with prior hospitalizations, parent traumatic stress screener (PCL-6), and child age. Outcomes included child emotional distress and quality of life; parent emotion, traumatic stress symptoms (IES-R), well-being; and family function. Mediation effects were estimated using ANCOVA, with indirect effects estimated using the percentile bootstrap approach. Moderation effects were tested by including appropriate interaction terms in models., Results: No significant mediation effects were observed. Child distress with prior hospitalizations moderated AME effects for IES-R intrusion subscale scores at T2 ( P  = .01) and avoidance subscale scores at T3 ( P  = .007). Traumatic stress screener scores (PCL-6) moderated intervention effects for IES-R hyperarousal subscale scores at T2 ( P  = .01). There were no moderation effects for child age., Conclusions: AME is a promising intervention for mitigating traumatic stress symptoms and supporting well-being in parents of children with cancer, particularly for parents who screen high for traumatic stress and whose children are more highly distressed with hospitalization., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Parents of adolescents and young adults (AYAs) with cancer offer primary support to their children and often experience their own high levels of distress, affecting parent-AYA communication and quality of life., Objective: To reduce parent distress and improve communication during high-risk cancer treatment, we examined efficacy of a self-care and communication intervention for parents and indirect benefit for AYAs receiving a therapeutic music video (TMV) intervention., Methods: In this study, we conducted a multisite, randomized controlled trial with AYAs and parents enrolled as dyads (n = 110). Parents were randomized to intervention or low-dose control; all AYAs received TMV. Data collection occurred at baseline, 2 weeks post intervention (T2), and 90 days post intervention (T3)., Results: There were no significant between-group differences on primary outcomes for parents or AYAs. We did find significant differences favoring the parent intervention group on parenting confidence at T2 and marginally better outcomes for family adaptability/cohesion at T3. Both groups exhibited significant within-group improvement for parent distress (state anxiety, T3; perceived stress, T2 and T3; mood, T3), state anxiety (T2) intervention only, and family strengths control group only. Qualitative data demonstrate the parent intervention raised self-awareness and parent confidence in the short term., Conclusion: Parents found their intervention helpful. Absence of significant results may be due to short intervention duration, need for tailored content, underpowered sample, and potential indirect parent benefit from AYA participation in TMV. The parent intervention did not provide an indirect benefit for AYAs., Implications for Nursing: Parents identified their own need for communication and support from nurses. Nurses can optimize AYA care by attending to parent needs through supportive listening and encouraging self-care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.)

Objectives: Health care is a high-risk industry. To improve communication about daily events and begin the journey toward a high reliability organization, the Riley Hospital for Children at Indiana University Health implemented a daily safety brief., Methods: Various departments in our children's hospital were asked to participate in a daily safety brief, reporting daily events and unexpected outcomes within their scope of responsibility. Participants were surveyed before and after implementation of the safety brief about communication and awareness of events in the hospital. The length of the brief and percentage of departments reporting unexpected outcomes were measured., Results: The analysis of the presurvey and the postsurvey showed a statistically significant improvement in the questions related to the awareness of daily events as well as communication and relationships between departments. The monthly mean length of time for the brief was 15 minutes or less. Unexpected outcomes were reported by 50% of the departments for 8 months., Conclusions: A daily safety brief can be successfully implemented in a children's hospital. Communication between departments and awareness of daily events were improved. Implementation of a daily safety brief is a step toward becoming a high reliability organization.

Objectives: To examine the feasibility/acceptability of a parent-delivered Active Music Engagement (AME + P) intervention for young children with cancer and their parents. Secondary aim to explore changes in AME + P child emotional distress (facial affect) and parent emotional distress (mood; traumatic stress symptoms) relative to controls., Methods: A pilot two-group randomized trial was conducted with parents/children (ages 3-8 years) receiving AME + P ( n  =  9) or attention control ( n  =  7). Feasibility of parent delivery was assessed using a delivery checklist and child engagement; acceptability through parent interviews; preliminary outcomes at baseline, postintervention, 30 days postintervention., Results: Parent delivery was feasible, as they successfully delivered AME activities, but interviews indicated parent delivery was not acceptable to parents. Emotional distress was lower for AME + P children, but parents derived no benefit., Conclusions: Despite child benefit, findings do not support parent delivery of AME + P., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: To reduce the risk of adjustment problems associated with hematopoietic stem cell transplant (HSCT) for adolescents/young adults (AYAs), we examined efficacy of a therapeutic music video (TMV) intervention delivered during the acute phase of HSCT to: 1) increase protective factors of spiritual perspective, social integration, family environment, courageous coping, and hope-derived meaning; 2) decrease risk factors of illness-related distress and defensive coping; and 3) increase outcomes of self-transcendence and resilience., Methods: This was a multisite randomized, controlled trial (COG-ANUR0631) conducted at 8 Children's Oncology Group sites involving 113 AYAs aged 11-24 years undergoing myeloablative HSCT. Participants, randomized to the TMV or low-dose control (audiobooks) group, completed 6 sessions over 3 weeks with a board-certified music therapist. Variables were based on Haase's Resilience in Illness Model (RIM). Participants completed measures related to latent variables of illness-related distress, social integration, spiritual perspective, family environment, coping, hope-derived meaning, and resilience at baseline (T1), postintervention (T2), and 100 days posttransplant (T3)., Results: At T2, the TMV group reported significantly better courageous coping (Effect Size [ES], 0.505; P = .030). At T3, the TMV group reported significantly better social integration (ES, 0.543; P = .028) and family environment (ES, 0.663; P = .008), as well as moderate nonsignificant effect sizes for spiritual perspective (ES, 0.450; P = .071) and self-transcendence (ES, 0.424; P = .088)., Conclusions: The TMV intervention improves positive health outcomes of courageous coping, social integration, and family environment during a high-risk cancer treatment. We recommend the TMV be examined in a broader population of AYAs with high-risk cancers., (© 2013 American Cancer Society.)

Outcome for the vast majority of high-risk neuroblastoma patients with refractory or relapsed disease is dismal. We report two high-risk patients who remain progression-free for more than 113 and 18 months following the diagnosis of refractory/relapsed disease who were treated with surgery alone. Complete resolution of a refractory thoracic mass and relapsed liver nodules was observed in one patient. The refractory/relapsed disease in the second patient has remained stable. In both cases, the tumor showed histologic evidence of neuroblastoma maturation. These cases demonstrate that refractory/relapsed neuroblastoma is clinically heterogeneous and highlight the need for better biomarkers to optimize patient care., (Copyright © 2012 Wiley Periodicals, Inc.)

The mortality in the ICU for pediatric HSCT recipients remains high. Early pulmonary complications continue to be an obstacle to the survival. We hypothesize OI is a predictor for mortality in critically ill pediatric HSCT recipients. Retrospective review of pediatric HSCT recipients between 2002 and 2010 who required intensive care during the same hospital admission as their transplant. Twenty-eight patients accounted for 31 ICU admissions. Twenty-six (84%) admissions required mechanical ventilation. Ten (38%) mechanically ventilated admissions were placed on HFOV. Mortality of those mechanically ventilated was 70%. An OI ≥ 20 at any point during ventilation was associated with 94% mortality, while an OI ≥ 25 had 100% mortality. There was a significant association between maximum OI at any point during mechanical ventilation and ICU mortality, with the odds of dying increasing by 13% for each unit increase of max OI (OR = 1.13, 95% CI = 1.01-1.26, p = 0.03). An OI of 20 had a sensitivity of 0.89 and specificity of 0.83 for predicting mortality. OI has a strong association with ICU mortality among pediatric stem cell recipients., (© 2012 John Wiley & Sons A/S.)

Background: Pre-allogeneic hematopoietic stem cell transplantation (aHSCT) and post-aHSCT lung function of 41 eligible patients at Riley Hospital for Children were assessed to identify risk factors for post-aHSCT morbidity and mortality., Observations: One year post-aHSCT pulmonary function tests were significantly lower compared with baseline. These findings recovered at 2 years post-aHSCT. Refractory disease before aHSCT correlated with lower pulmonary function tests after aHSCT. Graft-versus-host disease was significantly associated with higher post-aHSCT residual volume. Importantly, low pre-aHSCT carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume was predictive of death., Conclusions: Among survivors, lung function improves over time after pediatric aHSCT. Measurement of carbon monoxide diffusing capacity adjusted for hemoglobin and alveolar volume before pediatric aHSCT should be further investigated as a predictor of pulmonary dysfunction and mortality.

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease., (Copyright 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Total body irradiation (TBI)-based conditioning regimens for pediatric patients with acute myelogenous leukemia (AML) beyond first complete remission (CR1) are controversial. Because the long-term morbidity of busulfan (Bu)-based regimens appears to be lower, determining efficacy is critical. We retrospectively evaluated 151 pediatric patients with AML beyond CR1, comparing outcomes in 90 patients who received a TBI-based conditioning regimen and 61 patients who received a Bu-based conditioning regimen. There were no differences between the 2 groups with respect to age, sex, duration of CR1, time from most recent remission to transplantation, or donor source. The probability of relapse at 2 years also did not differ between the 2 groups (26% and 27%, respectively; P=.93). No significant difference in event-free survival (EFS) (P=.29) or overall survival (OS) (P=.11) was noted between the 2 groups. These findings were supported by a multivariate analysis in which TBI was not associated with improved EFS (hazard ratio [HR]=1.17; 95% confidence interval [CI]=0.66-2.10; P=.58) or OS (HR=1.42; 95% CI=0.76-2.64; P=.27). Shorter CR1 and receiving an HLA-mismatched transplant adversely affected EFS and OS in this cohort. Our study provides no evidence of an advantage to using TBI in children with AML beyond CR1. A prospective, randomized study is needed to confirm these results.

SCN is characterized by neutropenia, life-threatening infections, and progression to myelodysplastic syndrome/acute myelogenous leukemia. The only curative option is SCT, but few reports using UCB as a stem cell source exist. Here, we report two SCN patients transplanted with UCB. Patient 1 was transplanted at seven yr of age due to increasingly large injections of G-CSF (>100 microg/kg/day) and the risk of developing leukemia. He engrafted promptly and is clinically well and immune reconstituted >2 yr post-transplant. Patient 2 underwent UCB SCT at nine months of age for recurrent severe infections, despite high doses of G-CSF. He rejected his first graft, having 100% host cells on day +35, and immediately underwent a second UCB SCT. He engrafted but experienced late graft rejection six months after the second transplant. He received a third UCB SCT following a more immunosuppressive conditioning regimen. His course was complicated by HHV-6 viremia and gut GVHD, but he is now clinically well and has 99% donor engraftment >20 months post-transplant. We conclude that UCB is an acceptable stem cell source for SCN patients, but conditioning must be adequately immunosuppressive to ensure engraftment in patients without prior chemotherapy.

Toxoplasmosis is an infrequent infection with a high mortality rate in hematopoietic stem cell transplant recipients, and is usually caused by reactivation of prior, latent infection upon intensive immunosuppression. We report a case of fatal disseminated toxoplasmosis, diagnosed at autopsy, in a 7-year-old boy who received a cord blood graft for recurrent acute lymphoblastic leukemia. This case represents both the first reported case of toxoplasmosis in an engrafted cord blood recipient, and also of graft failure due to toxoplasmosis. Recommendations for toxoplasmosis diagnosis, treatment, and prophylaxis in stem cell transplant recipients are reviewed.

Aims: To identify risk factors which predispose children to develop liver dysfunction (LD) during the initial 100 days following hematopoietic stem cell transplantation (HSCT)., Methods: Retrospective analysis of all patients (<21 yr) who had undergone HSCT from July 1998 to June 2003. LD was defined by the presence of clinical jaundice and/or elevated alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) (1.5 times normal)., Results: One hundred and six patients underwent HSCT during the study period. LD was seen in 91 (85.5%) patients and the majority (58.2%) had moderate to severe LD. The primary cause of LD could be ascertained in 2/3 of patients and was multifactorial in the rest. The odds ratio and 95% CI for risk factors associated with LD following HSCT on univariate analysis were as follows: allogeneic source of stem cells 4.2 (1.2-14.2), engraftment >12 days 4.3 (1.3-14.2), total parenteral nutrition >35 days 8.2 (1.1-66.2), pretransplant ALT >40 U/L 7.4 (0.9-58.6), use of cyclosporine and methotrexate 9.5 (1.2-77.9), and use of amphotericin-B 3.1 (0.9-10.6). On multivariate analysis only elevated pre transplantation ALT and delayed engraftment were associated with post-HSCT LD. LD was seen in all 13 patients who died within 100 days following HSCT, and it was felt to be the primary cause of death in six (46%) patients. The factors associated with increased risk of mortality were: allogeneic source of stem cells, delayed engraftment (>18 days), higher mean peak GGT (>250 U/L), and total bilirubin (>6 mg/dL)., Conclusion: LD was common and severe in the majority of children following HSCT. Risk of LD was higher in children who had elevated pretransplantation ALT or had delayed engraftment. LD contributes significantly to morbidity and mortality following HSCT.

Unrelated cord blood (UCB) hematopoietic stem cells were serially transplanted into two human leukocyte antigen (HLA)-identical siblings with T cell, B cell, natural killer cell severe combined immunodeficiency. Brother A received a 4/6-matched, HLA DRbeta1-identical but class I-disparate UCB graft after myeloablative dosages of busulfan, melphalan, and antithymocyte globulin. He experienced complete donor chimerism, severe acute gastrointestinal graft-versus-host disease (GVHD), and limited chronic skin GVHD that resolved with treatment. Two years later, brother B received unfractionated marrow from brother A after reduced-intensity conditioning with cyclophosphamide and antithymocyte globulin. Brother B experienced mixed-donor (i.e. original UCB) chimerism and no histologically documented GVHD. Both brothers are clinically well; brother A is in a fully immunologically reconstituted state. The uneventful course and progressive increase in donor chimerism after the second transplantation indicates that hematopoietic cells derived from the older brother's marrow engrafted without causing GVHD, suggesting that acquired tolerance to disparate unrelated HLA antigens was achieved.

Purpose: To investigate whether response to induction therapy, evaluated by metaiodobenzylguanadine (MIBG) and bone scintigraphy, correlates with event-free survival (EFS) in children with high-risk neuroblastoma (NB)., Patients and Methods: Twenty-nine high-risk NB patients were treated prospectively with an intensive induction regimen and consolidated with three cycles of high-dose therapy with peripheral blood stem-cell rescue. The scintigraphic response was evaluated by MIBG and bone scans using a semi-quantitative scoring system. The prognostic significance of the imaging scores at diagnosis and following induction therapy was evaluated., Results: A trend associating worse 4-year EFS rates for patients with versus without osteomedullary uptake on MIBG scintigraphs at diagnosis was seen (35% +/- 11% v 80% +/- 18%, respectively; P =.13). Similarly, patients with positive bone scans at diagnosis had worse EFS than those with negative scans, although the difference did not receive statistical significance (34% +/- 10% v 83% +/- 15%, respectively; P =.06). However, significantly worse EFS was observed in patients with a postinduction MIBG score of >/= 3 compared to those with scores of less than 3 (0% v 58% +/- 11%; P =.002). There was no correlation between bone scan scores and outcome following induction therapy., Conclusion: MIBG scores >/= 3 following induction therapy identifies a subset of NB patients who are likely to relapse following three cycles of high-dose therapy with peripheral blood stem-cell rescue, local radiotherapy, and 13-cis-retinoic acid. Alternative therapeutic strategies should be considered for patients with a poor response to induction therapy.

Purpose: To investigate whether high-dose therapy with hematopoietic stem-cell rescue (HSCR) will improve survival for patients with relapsed Wilms' tumor., Patients and Methods: Thirteen children with relapsed Wilms' tumor were treated with one or two cycles of high-dose chemotherapy (HDT) followed by autologous HSCR. Twelve of 13 patients received reinduction chemotherapy before HDT and HSCR. The median age at diagnosis was 4.8 years, and the median time to relapse was 12 months. The histology was favorable in 12 of 13 patients. The ablative regimens included: (1) thiotepa (TT)/cyclophosphamide (CTX)/carboplatin (CP; n = 2); (2) TT/CTX (n = 5); (3) TT/etoposide (ETP; n = 1); and (4) CP/ETP/CTX (n = 1). Four patients received two cycles of HDT and HSCR. Cycle 1 consisted of CP/ETP/CTX, and melphalan/CTX were used in cycle 2., Results: Seven of 13 patients are alive without evidence of disease, with a median follow-up of 30 months. The 4-year estimated event-free survival (EFS) rate is 60% (95% CI, 0.40 to 6.88), and the overall survival (OS) at 4 years is 73% (95% CI, 0.40 to 6.86). There was no transplant-related mortality. All patients engrafted to an absolute neutrophil count 500/microL at a median of 13 days (range, 8 to 62 days) and had an unsustained platelet count > 20.0 micro at a median of 16 days (range, 10 to 202 days)., Conclusion: Our results suggest that HDT with HSCR is an effective treatment for patients with Wilms' tumor who experience relapse.

Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an accepted treatment for both thalassemia and sickle cell disease (SCD). However, it is associated with decided risk of both transplant-related mortality (TRM) and chronic graft-versus-host disease (GVHD). We analyzed 44 patients (median age, 5 years; range, 1-20 years) given an allogeneic related cord blood transplant for either thalassemia (n = 33) or SCD (n = 11). Thirty children were given cyclosporin A (CsA) alone as GVHD prophylaxis, 10 received CsA and methotrexate (MTX), and 4 patients received other combinations of immunosuppressive drugs. The median number of nucleated cells infused was 4.0 x 10(7)/kg (range, 1.2-10 x 10(7)/kg). No patient died and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range, 4-76 months). Only one patient with SCD did not have sustained donor engraftment as compared with 7 of the 33 patients with thalassemia. Three of these 8 patients had sustained donor engraftment after BMT from the same donor. Four patients experienced grade 2 acute GVHD; only 2 of the 36 patients at risk developed limited chronic GVHD. The 2-year probability of event-free survival is 79% and 90% for patients with thalassemia and SCD, respectively. Use of MTX for GVHD prophylaxis was associated with a greater risk of treatment failure. Related CBT for hemoglobinopathies offers a good probability of success and is associated with a low risk of GVHD. Optimization of transplantation strategies could further improve these results.

In this retrospective study, we review the immune reconstitution of children undergoing autologous hematopoietic stem cell transplantation. A total of 125 patients underwent autologous transplantation between 1992 and 2000. The report includes data on 58 patients. Data were not available on the remaining patients who either died before testing or data were not obtained. The parameters evaluated include: (a) immunophenotype by flow cytometry to quantify lymphocyte subpopulations (b) mitogen stimulation assays, and (c) quantitative immunoglobulins. The analysis reveals that CD3+ cells did not reach the normal range during the first year post-transplant. The median percentage of CD4+ cells was below normal up to 6 months post-transplant, while the absolute number remain low throughout the first year. The CD8+ percentage and absolute numbers remain normal at all times post-transplant. The CD19+ cells were also normal post-transplantation. The mitogen lymphocyte stimulation was normal in 27 out of 31 patients tested after 6 months post-transplant. Our analysis of immune reconstitution shows a similar pattern to previous studies with a faster recovery of the CD4/CD8 ratio, especially in those patients who did not receive TBI. In conclusion, the observed deficiencies are transient and have very little clinical significance because, historically, the rate of serious infections is low despite prolonged immune suppression. The recovery post-autologous transplant is fast.

Hepatoblastoma is the most common liver tumor diagnosed in children. Children with persistently unresectable disease, metastatic disease at presentation, recurrent disease, or slowly declining alpha-fetoprotein levels are at high risk for recurrence, exhibit an extremely poor prognosis, and are in desperate need of novel therapeutic agents and strategies. Four high-risk patients were treated. One patient with a local recurrence was treated with irinotecan followed by orthotopic liver transplant. Three patients were treated with tandem high-dose chemotherapy (HDT) with autologous stem cell rescue (two with primary metastatic disease and one with recurrent disease). All three of the patients treated with HDT had relapse (two of them subsequently received irinotecan); the remaining patient underwent surgical resection of a solitary recurrent pulmonary metastasis. Irinotecan demonstrated significant antitumor effects in all three treated patients and was well tolerated. None of the three patients treated with HDT remained disease-free, although the patient who underwent surgical resection of a solitary recurrent pulmonary metastasis remains disease-free 6 years from diagnosis. Further exploration of the use of irinotecan is warranted in high-risk patients with hepatoblastoma.

Umbilical cord blood (UCB) has become a frequent source of allogeneic hematopoietic stem cells for transplantation. Of theoretical concern is a potential decrease in the graft vs. leukemia (GvL) effect, given the lesser degree of graft vs. host disease (GvHD) with this donor source. We report a case of recurrent acute non-lymphoblastic leukemia (ANLL) following stem cell transplantation with unrelated mismatched UCB, which responded to the induction of GvHD. The response was documented both morphologically and by evaluation of chimeric engraftment by molecular DNA techniques. In addition, WT-1, a purported marker of minimal residual disease in acute leukemia, correlated with remission status in this patient. In summary, the GvL effect is seen with allogeneic UCB transplantation and has the potential to be induced along with GvHD.

Purpose: To investigate whether intensive induction therapy followed by triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue and local irradiation will improve event-free survival for patients with high-risk neuroblastoma., Patients and Methods: From August 1995 to January 2000, 25 consecutive newly diagnosed high-risk neuroblastoma patients and one child with recurrent MYCN-amplified disease were enrolled onto the Chicago Pilot II Protocol. After induction therapy and surgery, peripheral-blood stem cells were mobilized with three cycles of high-dose cyclophosphamide and granulocyte colony-stimulating factor. Patients then underwent triple-tandem cycles of high-dose therapy with peripheral-blood stem-cell rescue followed by radiation to the primary site., Results: Twenty-two of the 26 patients successfully completed induction therapy and were eligible for the triple-tandem consolidation high-dose therapy. Sufficient numbers of peripheral-blood stem cells were collected in all but one patient. Seventeen patients were able to complete all three cycles of high-dose therapy and peripheral-blood stem-cell rescue, two patients completed two cycles, and three patients completed one cycle. There was one toxic death, and one patient died from complications of treatment for graft failure. With a median follow-up of 38 months, the 3-year event-free survival and survival rates are 57% +/- 11% and 79% +/- 10%, respectively., Conclusion: The results of this pilot study demonstrate that it is feasible to intensify consolidation with triple-tandem high-dose chemotherapy and peripheral-blood stem-cell rescue and local irradiation, and suggest that this treatment strategy may lead to improved survival for patients with high-risk neuroblastoma.

In order to monitor the clinical outcome of pediatric patients with leukemia following allogeneic hematopoietic transplantation, tests of variable number of tandem repeat (VNTR) and sex determination by quantitative polymerase chain reaction (PCR) were performed. PCR results combined with the blast counts from 21 leukemia patients were analyzed. Complete chimerism (100% donor cells) was found in 15 cases with remission, and incomplete chimerism in six cases with relapse. In the majority of cases, complete chimerism was always associated with no detectable blasts, while blasts were often detected in association with incomplete chimerism. There is significant correlation (P<0.0001) between the percentage of donor DNA and blast percentage in these patients. Early detection of incomplete chimerism may therefore predict a poor prognosis. In one patient (case 15), a differing percentage of donor DNA was observed between samples of bone marrow and peripheral blood collected on the same day. This may be due to the fact that allogeneic stem cells proliferate at different rates depending on their environment (bone marrow or peripheral blood). In addition, 100% donor cells found in the peripheral blood may not reflect the number of cells in the bone marrow. In case 17, asynchronous engraftment of donor cells was present between the white and red blood cell lineages, indicating that the degree of chimerism may not be the same in all cell lineages. At the time of this report, the significance of this observation is unknown and needs further investigation.

We describe the development of a pediatric outpatient transplant program and our initial experience with autologous and allogeneic transplants performed partially or completely in the outpatient setting. Forty-eight autologous and seven allogeneic transplants have been performed in our institution in the outpatient setting between June 1994 and July 2000. The ablation used for the autologous outpatient transplants was VP-16 1000 mg/m2/ day as a continuous infusion for 2 days and Carboplatinum 667mg/m2/day for 2 days. The autologous inpatient transplants received Thio-tepa 300-mg/ m2per day x 3 days and cyclophosphamide 60 mg/kg/day for 4 days. For those patients who received an immune-ablative allogeneic outpatient transplant, the regimen consisted of Fludarabine 30 mg/m2/day for 6 days, followed by busulfan for children less than five years of age 1 mg/kg/dose x 8 doses and for those five years and older 0.8 mg/kg/dose x 8 doses, followed by ATG 40mg/kg/day x 4 days. Engraftment was complete in all transplants achieving an ANC >500 for the outpatient transplant in 15 days (10-35) vs. the inpatient in 15 days (14-58). This was not statistically significant. They achieved un-sustained platelets >20.0 by day 19 (14-58) for the outpatients and day 32 10-64) for the inpatient. The allogeneic immune ablative transplants were considered engrafted when their VNTRs were greater that 30% which was achieved at a median of 13 days (10-27). The economic data showed a statistically significant decrease in charges and direct costs between the outpatient (median charges $30 775, direct costs $8 389) and the inpatient (median charges $99 838, direct costs $42 757) transplants (p0.001). There was no difference in morbidity and mortality between the two groups but the use of empiric amphotericin B was markedly decreased in the outpatient transplants. In conclusion it is feasible and less costly to perform autologous hematopoietic stem cell transplants in the outpatient setting with no increase in morbidity and mortality. For the allogeneic transplants there is not yet enough data to establish a similar conclusion.

Objectives: To describe the morphologic characteristics of skin lesions, extent of extracutaneous disease, and outcomes in patients with neonatal presentation of Langerhans cell histiocytosis (LCH), and to examine clinical predictors of disease prognosis., Design: Retrospective validation cohort study. Maximum duration of follow-up was 10 years., Setting: A tertiary care children's hospital in Chicago, Ill., Patients: Nineteen children with cutaneous findings in the first 4 weeks of life and subsequently diagnosed with LCH based on compatible tissue histologic analysis, confirmed by electron microscopy and/or immunohistochemical analysis., Main Outcome Measure: Cutaneous lesion morphologic characteristics, extracutaneous manifestations, treatments, and outcomes were tabulated and compared., Results: The most common initial skin lesion was erythematous, often crusted, vesiculopustules. Skin lesion morphologic traits did not correlate with extent of extracutaneous disease. One third of patients had disease limited to the skin and/or mucous membranes. All of these patients are alive and well, and 1 has developed diabetes insipidus. Twelve of the 19 patients had multisystem disease, and 2 died of disease. The results of a multiorgan workup performed at the time of diagnosis were predictive of which patients in this cohort manifested multisystem disease. The overall incidence of diabetes insipidus was 21%., Conclusions: Vesiculopustular lesions are common in congenital/neonatal LCH, but the morphologic characteristics of lesions are not helpful in predicting the extent of disease. A multiorgan evaluation at the time of diagnosis may be predictive of the probability of multisystem involvement with LCH.

Epstein-Barr virus-associated post-transplant lymphoproliferative disorder (PTLD) has been well described as a complication following allogeneic stem cell transplantation but has only recently been reported following umbilical cord blood (UCB) transplant. We report the case of a child transplanted with unrelated mismatched UCB for juvenile chronic myelogenous leukemia (JCML) who developed EBV-associated PTLD, which was confirmed pathologically, 139 days following stem cell infusion. There was no clinical response to reduction of immune suppression, high-dose acyclovir, or alpha interferon. The patient died 160 days after transplantation. EBV was detected by polymerase chain reaction in the cord blood unit used for transplantation. This case demonstrates that EBV-associated PTLD can occur following mismatched unrelated UCB transplant and may be related to transmission of EBV infection by donor lymphocytes.

Background: Natural killer (NK) cell lymphomas are rapidly fatal malignancies that to the authors' knowledge are rare in children. In the current study, the authors report the cases of two boys with NK cell lymphomas with refractory disease who both were salvaged with high dose chemotherapy and stem cell transplantation and compare these patients with those in the published experience., Methods: A comprehensive literature review was performed to identify other cases of pediatric patients with NK cell lymphomas, their treatment, and outcome., Results: One of the patients in the current study developed two recurrences and the other patient experienced early disease progression during front-line treatment. Both then were treated with high dose chemotherapy followed by stem cell rescue. At last follow-up, the patients remained free of disease at 15 months and 16 months, respectively, after transplantation (48 months and 22 months, respectively, from the time of diagnosis). In addition to the 2 patients in the current study, the authors found 13 pediatric patients reported in the literature to date. Of the 7 patients with localized (Stage I-II) disease, 5 patients (71%) were reported to be alive 1-107 months after diagnosis. Of the 6 patients with Stage IV disease, only the 2 patients who received high dose chemotherapy and stem cell rescue (33%) were alive at the time of last follow-up (at 30 months and 12 months, respectively). Including the patients reported in the current study, 9 of 15 children with NK cell lymphoma (all stages) (60%) were reported to be alive at the time of last follow-up., Conclusions: Although pediatric NK cell lymphomas rapidly can become fatal, it appears that high dose chemotherapy followed by stem cell transplantation is effective therapy, especially in patients with advanced or resistant disease. Further follow-up is needed to determine whether this treatment approach will be curative., (Copyright 2001 American Cancer Society.)

Eighty-three pediatric patients underwent autologous peripheral blood stem cell transplants at a single institution and were included in a study evaluating the correlations between five engraftment parameters and the time to both neutrophil and platelet recovery. The parameters included: the number of nucleated cells per kg (TNC/kg), the absolute CD34+ cell content per kg (CD34+/kg), the number of mononuclear cells per kg (MNC/kg), the number of BFU-E/kg, and the number of CFU-GM/kg. A two-tailed Mann-Whitney test (alpha = 0.05) was used to determine if there were significant differences between patients with neuroblastoma (n = 45) and patients with other diagnoses (n = 38). No statistically significant differences existed between neuroblastoma patients and patients with other diagnoses. Therefore, the two groups of patients were pooled together. Data were analyzed using both a univariate and multivariate correlation method and Student's t-test (alpha = 0.05). Two statistically significant logarithmic relationships were found. The first relationship was between MNC/kg and time to ANC reconstitution (P = 0.05). The second relationship was between CFU-GM/kg and time to platelet recovery (P = 0.01). Based on the statistical data, we conclude that there is no correlation between nucleated cell dose, CD34+ cell dose, and BFU-E content with either neutrophil or platelet recovery. Accordingly, in this study MNC cell dose per kilogram was the most important parameter predicting the length of time between graft infusion and neutrophil recovery while CFU-GM content per kilogram was the most important parameter predicting the length of time until platelet recovery.

Hematopoietic stem-cell transplantation (HSCT) is an effective mode of therapy in pediatrics for the treatment of both malignant and non-malignant disorders. We compared the course of children transplanted with unrelated umbilical cord blood (UCB) to those transplanted with allogeneic sibling bone marrow (BM) for bone marrow failure syndromes. Thirteen patients with a median age of 6.3 years were transplanted for the following diseases between April 1992 and November 1997: myelodysplastic syndromes, aplastic anemia, Diamond-Blackfan anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, osteopetrosis and dyskeratosis congenita. The stem cell source was BM in ten patients and UCB in three. We retrospectively examined the conditioning regimens, stem cell source and dose, days to engraftment, survival and complication rate to see whether there was a significant advantage in using one source over the other. The median time to an absolute neutrophil count > 500 per microL was 25 days for UCB patients and 16 days for BM patients. The median time to a platelet count > 20,000 per microL was 55 days for UCB patients and 22 days for BM patients. The 100-day mortality was 66% in UCB patients and 20% in BM patients. The overall mortality rates were 66% and 40%, respectively. Three patients died prior to engraftment. Seven patients (54%) were still alive as of May 1999 with a median follow-up of 1574 days post-transplant. The patients transplanted with BM had faster engraftment and lower rates of graft-versus-host disease, 100-day mortality and overall mortality. HLA-matched sibling BM is preferred as a source but transplantation using unrelated UCB is still an option in treating pediatric bone marrow failure syndromes.

Autologous and allogeneic PBSC collection and cryopreservation have been shown to be feasible in the pediatric population. This technique may be associated with complications, including volume overload and DMSO toxicity. To decrease these risks, we developed a technique by which PBSC are collected over a 2-day period and pooled prior to cryopreservation. PBSC are harvested on day 1 and stored with tissue culture medium on a rocker at ambient temperature. On day 2, a second PBSC harvest is performed, and the two harvests are pooled, separated on a Ficoll gradient in a semiautomatic closed system, and frozen with 10% DMSO after a soft spin for volume reduction. Cells from each day's harvest are tested for cell count and viability. A total of 36 collections in 26 patients were performed. This technique resulted in a 73%+/-0.0% reduction in volume (mean +/- SEM) and an 88%+/-0.9% depletion of RBC. Mononuclear cell (MNC) count recovery was 88%+/-2.6%, and the MNC dose delivered to the patient was 3.1+/-0.6x10(8) cells/kg. Cell viability was >98% before and after processing. Seventeen patients have been transplanted thus far, and all these patients engrafted with minimal toxicity. These data indicate that storing PBSC for up to 24 h after harvest does not decrease PBSC viability or delay engraftment.

Background: Animal studies performed on mice have shown that the number of cells infused following ablative regimens affected the speed and quality of engraftment. Similar studies on humans have resulted in contradicting results. We present our experience assessing multiple parameters., Methods: Fifty-eight pediatric patients underwent allogeneic BM transplants at a single institution and were included in a study evaluating the correlation between five engraftment parameters and the time to either neutrophil, or platelet recovery. The parameters included: the number of total nucleated cells per kg (TNC/kg), the absolute CD34(+) cell content per kg (CD34(+)/kg), the number of mononucleated cells per kilogram (MNC/kg), the number of NFU-E/kg and the number of colony-forming units-granulocyte-macrophage (CFU-GM)/kg. Data were analyzed using both multivariate and univariate correlation method and a Student's t-test., Results: Three satistically-significant logarithmic relationships were found. The first relationship was between TNC/kg and time to ANC reconstitution (p=0.01). The second and third relationship correlated the CD34(+) cell dose with both ANC and platelet recovery., Discussion: Based on the statistical data, we conclude that there is no correlation between MNC dose, CFU-GM/kg and BFU-E/kg content, with either neutrophil or platelet recovery. However, TNC and CD34(+) cell dose per kilogram are the most important parameters predicting the length of time between graft infusion and neutrophil recovery, while CD34(+)/kg is the most important parameter predicting the length of time until platelet recovery. We recommend the use of CD34(+) cell dose as the most reliable parameter to determine the size of the graft in pediatric hematopoietic stem cell recipients.

Thirty-five pediatric patients, 1-16 years of age (median 6.3 years), with neoplastic solid tumors (n=32) or acute leukemia (n=3) underwent peripheral blood stem cell (PBSC) harvest and transplantation at Children's Memorial Hospital between September 1992 and April 1997. A median of four phereses were performed on each patient. Blood samples from 34 of the 35 patients were harvested through existing double-lumen central catheters, using either a Fenwal CS-3000 or COBE Spectra pheresis machine. The pheresis procedures were well tolerated overall. A median of 3.7 x 10(6)/kg CD34+ cells were infused (range, 0.2-15.5 x 10(6)/kg), and all patients engrafted. The median time to an absolute neutrophil count >500/microL was 13 days (range, 9-44 days) and to a platelet count >20,000/microL was 21 days (range, 9-210 days). Two patients died from transplant-related complications. Patients were discharged from the hospital after a median of 22 days (range, 15-64 days). Twenty of the 35 patients are alive, 17 of whom remain disease-free with a median follow-up of 1144 days. According to this study, PBSCs can be successfully harvested and re-infused for marrow reconstitution after myeloablative therapy in children for a variety of pediatric malignancies with low morbidity and mortality.

A single institutional pilot study was conducted in which 12 poor-risk neuroblastoma (NB) patients were uniformly treated with multi-agent induction chemotherapy followed by myeloablative consolidation chemotherapy and unpurged peripheral blood stem cell (PBSC) rescue. In addition to using standard criteria for evaluating response to induction chemotherapy, tumor cell contamination of the peripheral blood and/or bone marrow was analyzed in seven patients by immunocytology using a panel of five anti-NB monoclonal antibodies. Seven patients had morphologic evidence of bone marrow disease at the time of diagnosis, and two additional patients had tumor cells detected in bone marrow samples by immunocytology prior to the second cycle of chemotherapy. After three cycles of chemotherapy, two of the 12 patients continued to have evidence of bone marrow disease. Samples from 29 PBSC harvests collected from nine patients were also analyzed for the presence of contaminating tumor cells by immunocytology. In each case, the stem cells were found to be free of tumor. Eleven of the 12 patients underwent myeloablative therapy and PBSC rescue; five patients remain alive without disease progression, 28+ to 53+ months from diagnosis, and six patients have developed recurrent disease. We conclude that PBSCs can be successfully harvested from children with NB, and used for hematopoietic reconstitution following myeloablative chemotherapy. However, more effective therapy for poor-risk NB patients is still urgently needed.