Pedro de Alarcon

Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: A report from the Pediatric Oncology Group

A retrospective data collection was performed on 29 children diagnosed with neuroblastoma and opsoclonus-myoclonus between 1983-1993 from Pediatric Oncology Group institutions. The aim was to describe neurologic outcome in children with neuroblastoma and opsoclonus-myoclonus. Age at diagnosis ranged from one month to 4 years (median age, 18 months). The duration of opsoclonus-myoclonus symptoms prior to the diagnosis of neuroblastoma ranged from 6 days to 17 months (median duration, 6 weeks). There was a prevalence of low stage disease according to the POG staging system: stage A (n = 18), stage B (n = 3), stage C (n = 7), stage D (n = 1). There was a predominance of paraspinal primary tumors. There was no case of Nmyc amplification (0/17), and 2/8 cases were diploid. Treatment for neuroblastoma consisted of surgery alone in 19/29 (18 stage A, 1 stage C in thorax), and surgery plus chemotherapy in 10/ 29. No patient received radiotherapy. Treatment for opsoclonus-myoclonus ranged varied. Six children received no treatment for opsoclonus-myoclonus. The following agents were used ACTH (n = 14), prednisone (n = 12), IV IgG (n = 6), immuran (n = 2), depakote (n = 1), and inderal (n = 1). Eighteen of 29 children (62%) had resolution of opsoclonus-myoclonus symptoms. The range of time for recovery was a few days to 3 years. However the majority recovered over several months. Twenty of 29 children (69%) had persistent neurologic deficits including speech delay, cognitive deficits, motor delay, and behavioral problems. Of the 9 children who had complete recovery of opsoclonus-myoclonus without neurologic sequelae, age at diagnosis and duration of symptoms were not different from the entire group. Interestingly, 6/9 children with complete recovery received chemotherapy as part of their treatment. In conclusion, persistent neurologic deficits are characteristic for children with neuroblastoma and opsoclonus-myoclonus. Treatment with chemotherapy may improve the neurologic outcome.

Dose-Intensive Response-Based Chemotherapy and Radiation Therapy for Children and Adolescents With Newly Diagnosed Intermediate-Risk Hodgkin Lymphoma: A Report From the Children's Oncology Group Study AHOD0031

PURPOSE The Childrens Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used. PATIENTS AND METHODS Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT. RESULTS Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment. CONCLUSION This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response.

Response-Dependent and Reduced Treatment in Lower Risk Hodgkin Lymphoma in Children and Adolescents, Results of P9426: A Report from the Children’s Oncology Group

Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.

Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA): a model for sustainable development in pediatric oncology.

Bridging the survival gap for children with cancer, between those (the great majority) in low and middle income countries (LMIC) and their economically advantaged counterparts, is a challenge that has been addressed by twinning institutions in high income countries with centers in LMIC. The long‐established partnership between a Central American consortium—Asociación de Hemato‐Oncología Pediátrica de Centro América (AHOPCA)—and institutions in Europe and North America provides a striking example of such a twinning program. The demonstrable success of this endeavor offers a model for improving the health outcomes of children with cancer worldwide. As this remarkable enterprise celebrates its 15th anniversary, it is appropriate to reflect on its origin, subsequent growth and development, and the lessons it provides for others embarking on or already engaged in similar journeys. Many challenges have been encountered and not all yet overcome. Commitment to the endeavor, collaboration in its achievements and determination to overcome obstacles collectively are the hallmarks that stamp AHOPCA as a particularly successful partnership in advancing pediatric oncology in the developing world. Pediatr Blood Cancer 2014;61:345–354.

Phase II Study of Weekly Gemcitabine and Vinorelbine for Children With Recurrent or Refractory Hodgkin's Disease: A Children's Oncology Group Report

PURPOSE The Childrens Oncology Group conducted this phase II study to assess the efficacy and toxicity of gemcitabine and vinorelbine (GV) in pediatric patients with heavily pretreated relapsed/refractory Hodgkins disease. Both agents have significant single-agent response rates in this setting. METHODS GV was given on days 1 and 8 of each 21-day treatment cycle: vinorelbine 25 mg/m(2)/dose administered via intravenous (IV) push before gemcitabine 1,000 mg/m(2)/dose IV over 100 minutes. Any patients who demonstrated a measurable response (complete response [CR], very good partial response [VGPR], or partial response [PR]) were considered to have experienced a response to GV. Response was evaluated after every two cycles. A two-stage minimax rule was used to test the null hypothesis that the response rate is <or= 40% against an alternative hypothesis of a response rate more than 65%. RESULTS Thirty eligible patients with a median age of 17.7 years (range, 10.7 to 29.4 years) were enrolled. All patients had received at least two prior chemotherapy regimens, and 17 patients had undergone prior autologous stem-cell transplantation. Hematologic toxicity was predominant in all treatment cycles. Nonhematologic grade 3 to 4 toxicity, including elevated hepatic enzymes and hyperbilirubinemia, was less common. Pericardial and pleural effusions developed in one patient after cycles 4 and 5 of GV, consistent with gemcitabine-induced radiation recall. There were no toxic deaths. Measurable responses were seen in 19 (76%) of 25 assessable patients (95% exact binomial CI, 55% to 91%), including six CRs, 11 VGPRs, and two PRs. CONCLUSION GV is an effective and well-tolerated reinduction regimen for children with relapsed or refractory Hodgkins disease.

A sustainable model for pediatric oncology nursing education in low-income countries

Effectiveness of a nurse educator in the pediatric oncology unit in Guatemala was assessed by measuring completion of an education course, chemotherapy and central line competency, continuing education, and cost. All newly hired nurses completed the education course. Of the nurses employed, 86% participated in the chemotherapy course, and 93% achieved competency; 57% participated in the central line course, and 79% achieved competency. The nurses completed a mean of 26 hours continuing education yearly. The annual direct cost of the educator (

Low-dose systemic thrombolytic therapy for deep vein thrombosis in pediatric patients.

244/nurse) was markedly less than other models. This is an effective and sustainable means to educate nurses in low‐income countries. Pediatr Blood Cancer 2012; 58: 163–166.

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study

Reduction of thrombus size and recanalization of vessels after deep vein thrombosis (DVT) are important goals to prevent recurrent thrombosis and development of postthrombotic syndrome. Thrombolysis is effective but concern for bleeding complications has limited its use in children. We retrospectively analyzed data for children with DVT treated with a low-dose systemic tissue plasminogen activator (tPA) regimen. Twenty-three pediatric patients (12 males and 11 females, median age 12 y) received low-dose systemic tPA, initiated at 0.03 to 0.06 mg/kg/h for a median of 24 hours (range 12 to 48 h). Of the 20 patients imaged within 24 hours of therapy, 6 (30%) showed partial to complete thrombus resolution. Eight patients subsequently received increased tPA at 0.12 mg/kg/h for an additional 24 hours (range 12 to 36 h). Six of these 8 (75%) patients responded to the increased dose. The overall response at the end of thrombolytic therapy was 59% (13/22). Two bleeding complications occurred without serious sequelae. Low-dose tPA administration leads to a substantial response rate although the risk of bleeding remains unclear. A prospective multicenter trial of low-dose thrombolytic therapy in children with acute DVT is warranted.

Effect of Chronic Erythropoietin Administration on Plasma Iron in Newborn Lambs

A Childrens Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59–83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61–95%; p = 0·32). Although not statistically different, results suggest IVB may be a promising combination.

Development of the hematopoietic system and disorders of hematopoiesis that present during infancy and early childhood.

Erythropoietin, the primary stimulator of erythropoiesis, represents an important potential therapy for the anemia of prematurity. Enhancement of the therapeutic benefit of recombinant human erythropoietin (rhEp) in very-low-birth-weight infants will require a better understanding of rhEps pharmacodynamic effects including its interaction with iron in stimulating erythropoiesis. The purpose of this study was to determine the effects of chronic rhEp administration on plasma iron levels and hematopoiesis using a twin lamb model. Nine pairs of twin lambs in which one twin was randomized to receive rhEp, and the other saline, were studied during a 1-week baseline and a subsequent 4- to 5-week treatment period. The effects of therapy on plasma iron levels and erythropoiesis were measured by integrating the areas under the concentration-time curves (AUC) of the study variables. During the rhEp treatment period, significantly greater negative daily AUCs were observed in the rhEp-treated lambs for plasma iron concentration (p = 0.0008), while significantly greater positive daily AUCs were observed for hemoglobin concentration (p = 0.04) and reticulocyte count (p = 0.02). In the rhEp-treated group, pretreatment iron concentrations were directly associated with the magnitude of the iron response during treatment such that the greater the pretreatment iron, the greater the daily AUC below the plasma iron concentration-time plot (r = -0.66, p = 0.05). For the placebo-treated group, this association tended toward, but did not achieve, statistical significance (r = -0.52, p = n.s.). These observations suggest that treatment of rapidly growing newborn lambs with rhEp results in increased iron utilization due to increased erythropoiesis and depends on iron status at the initiation of rhEp treatment. Use of the term neonatal lamb model offers advantages over studies in human infants for more detailed or invasive examinations of the interaction of iron and rhEp treatment.