Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: A report from the Children's Oncology Group.

BACKGROUND: The prognosis is poor for children and adolescents with recurrent osteosarcoma (OS). Glycoprotein non-metastatic B (gpNMB) is a glycoprotein highly expressed in OS cells. We conducted a phase II study of glembatumumab vedotin (GV), a fully human IgG2 monoclonal antibody (CR011) against gpNMB conjugated to the microtubule inhibitor, monomethyl auristatin E. PATIENTS AND METHODS: Patients aged ≥12 years and <50 years with relapsed or refractory OS were eligible. GV 1.9 mg/kg/dose was administered on day 1 of each 21 day cycle. Pharmacokinetics were mandatory in patients aged <15 years. gpNMB expression was measured by immunohistochemistry. The primary end-point was disease control at 4 months and Response Evaluation Criteria in Solid Tumours response. A 2-stage design was used to determine efficacy. RESULTS: Twenty-two patients were enrolled, and all were evaluable for response. Antibody-drug conjugate levels were detectable in patients, although small numbers limit comparison to adult data. The toxicities observed were similar to the previous studies with GV. The most common grade III adverse event was rash. One death from end organ failure occurred possibly related to GV. Of the 22 patients, one patient had a partial response, and two had stable disease. There was no correlation between gpNMB expression and response to GV. CONCLUSIONS: GV was well tolerated in this population. Although there was some antitumour activity, the extent of disease control in stage I did not meet the level required to proceed to stage II. TRIAL REGISTRATION NUMBERS: NCT02487979.

The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

BACKGROUND: The outcome for patients with metastatic rhabdomyosarcoma (RMS) remains poor. A previous Children's Oncology Group (COG) study (ARST0431) for patients with metastatic RMS produced no improvement in outcome using multiple cytotoxic agents in a dose-intensive manner. The authors report results from the subsequent COG study (ARST08P1), which evaluated the feasibility and efficacy of adding cixutumumab (insulin-like growth factor-1 monoclonal antibody) or temozolomide to the ARST0431 intensive chemotherapy backbone. METHODS: Two nonrandomized pilot studies were conducted in patients with metastatic RMS, initially to determine feasibility, and both pilots were expanded to assess efficacy. All patients received 54 weeks of chemotherapy, including vincristine/irinotecan, interval-compressed vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, and vincristine/dactinomycin/cyclophosphamide. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. In pilot 2, patients received oral temozolomide (100 mg/m2 ) daily for 5 days with irinotecan. All patients received radiation to the primary tumor and to metastatic sites. RESULTS: One hundred sixty-eight eligible patients were enrolled (97 on pilot 1 and 71 on pilot 2). Most patients were aged ≥10 years (73%), with alveolar histology (70%), and had bone and/or bone marrow metastases (59%). Toxicities observed in each pilot were similar to those reported on ARST0431. With a median follow-up of 2.9 years, the 3-year event-free survival rate was 16% (95% confidence interval, 7%-25%) with cixutumumab and 18% (95% confidence interval, 2%-35%) with temozolomide. CONCLUSIONS: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy for metastatic RMS was safe and feasible. Neither agent improved outcome compared with the same chemotherapy that was used on ARST0431.

A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies.

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Preventive antibiotics in pediatric patients with acute myeloid leukemia (AML).

BACKGROUND: Treatment of acute myeloid leukemia (AML) comes with a significant risk of life-threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life-threatening infections during treatment of childhood AML. PROCEDURES: This is a retrospective study on pediatric patients (aged 0-18 years) consecutively diagnosed with de novo AML and treated at a single institution from April 2005 through February 2013. Patients were treated on the Children's Oncology Group (COG) AAML0531 protocol or with a modified United Kingdom Medical Research Council (UK MRC) AML 10 regimen. Pertinent data were extracted from hard copy or electronic chart review. RESULTS: A total of 76 chemotherapy phases were analyzed from 29 patients. In each phase reported, preventive antibiotics were initiated when the daily absolute neutrophil count was <500 cells/mcl, before onset of fever. Seven episodes of bacteremia were documented with predominantly coagulase-negative staphylococci and viridans group streptococci. One infection-related death occurred, attributed to progressive respiratory failure occurring months after documented candidal pneumonia. CONCLUSIONS: Initiation of preventive antibiotics at the onset of absolute neutropenia was associated with no mortality from bacteremia. This preventive approach appears feasible and safe.

Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children's Oncology Group.

PURPOSE: This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors. PATIENTS AND METHODS: Patients with relapsed or refractory solid tumors were treated with 9 mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients. RESULTS: One hundred sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab. CONCLUSION: Cixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway.

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: a Children's Oncology Group study.

BACKGROUND: Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. PROCEDURE: Pemetrexed, at a dose of 1910 mg/m(2) , was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B(12) , daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. RESULTS: Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3-23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1-13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4-13) cycles, was observed in five patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n = 1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). CONCLUSIONS: Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.

Overcoming autopsy barriers in pediatric cancer research.

BACKGROUND: More than 13,000 children annually in the United States and Canada under the age of 20 will be diagnosed with cancer at a mortality approaching 20% 1,2. Tumor samples obtained by autopsy provide an innovative way to study tumor progression, potentially aiding in the discovery of new treatments and increased survival rates. The purpose of this study was to identify barriers to autopsies and develop guidelines for requesting autopsies for research purposes. PROCEDURE: Families of children treated for childhood cancer were referred by patient advocacy groups and surveyed about attitudes and experiences with research autopsies. From 60 interviews, barriers to autopsy and tumor banking were identified. An additional 14 interviews were conducted with medical and scientific experts. RESULTS: Ninety-three percent of parents of deceased children did or would have consented to a research autopsy if presented with the option; however, only half of these families were given the opportunity to donate autopsy tissue for research. The most significant barriers were the physicians' reluctance to ask a grieving family and lack of awareness about research opportunities. CONCLUSIONS: The value of donating tumor samples to research via an autopsy should be promoted to all groups managing pediatric cancer patients. Not only does autopsy tumor banking offer a potentially important medical and scientific impact, but the opportunity to contribute this Legacy Gift of autopsy tumor tissue also creates a positive outlet for the grieving family. Taking these findings into account, our multidisciplinary team has developed a curriculum addressing key barriers.

Rhabdomyosarcoma: review of the Children's Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies.

The prognosis for children and adolescents with rhabdomyosarcoma (RMS) has improved with refinements in multi-modal therapy. Since 1972, the Intergroup Rhabdomyosarcoma Study Group (now the Children's Oncology Group Soft-Tissue Sarcoma Committee) has conducted serial studies for RMS. This review describes the IRSG and COG experience with RMS, presents the current risk stratification definitions, and provides rationale for the current generation of COG RMS studies.

18F-FDG microPET imaging detects early transient response to an IGF1R inhibitor in genetically engineered rhabdomyosarcoma models.

BACKGROUND: Alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma (ERMS) are among the most common and most treatment resistant soft tissue sarcomas of childhood. Here, we evaluated the potential of (18)F-Fluorodeoxyglucose (FDG) as a marker of therapeutic response to picropodophyllin (PPP), an IGF1R inhibitor, in a conditional mouse model of ARMS and a conditional model of ERMS/undifferentiated pleomorphic sarcoma (UPS). PROCEDURE: Primary tumor cell cultures from Myf6Cre,Pax3:Fkhr,p53 and Pax7CreER,Ptch1,p53 conditional models of ARMS and ERMS/UPS were found to be highly sensitive to PPP (IC(50) values 150 and 200 nM, respectively). Animals of each model were then treated with 80 mg/kg/day PPP by intraperitoneal injection for 12 days and imaged by (18)F-FDG microPET. RESULTS: Tumor volumes on day 4 for PPP-treated ARMS and ERMS mice were lower than untreated control mouse tumor volumes, although treated tumors were larger than day 0. However, tumor FDG uptake was significantly reduced on day 4 for PPP-treated mice compared to pretreatment baseline or untreated control mice on day 4 (P < 0.05). Nevertheless, by day 12 tumor volumes and FDG uptake for treated mice had increased significantly, indicating rapidly evolving resistance to therapy. CONCLUSIONS: (18)F-FDG PET imaging is a potential imaging biomarker of molecular susceptibility to targeted agents early in treatment for this aggressive form of sarcoma, but may find best use serially for Phase I/II studies where chemotherapy and targeted agents are combined to cytoreduce tumors and abrogate Igf1r inhibitor resistance.

Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children's Oncology Group.

PURPOSE: A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES). PATIENTS AND METHODS: Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels-6 and 9 mg/kg-were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level. RESULTS: Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 µg/mL, which exceeded the effective trough concentration of 60 µg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES. CONCLUSION: Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.

Evasion mechanisms to Igf1r inhibition in rhabdomyosarcoma.

Inhibition of the insulin-like growth factor 1 receptor (Igf1r) is an approach being taken in clinical trials to overcome the dismal outcome for metastatic alveolar rhabdomyosarcoma (ARMS), an aggressive muscle cancer of children and young adults. In our study, we address the potential mechanism(s) of Igf1r inhibitor resistance that might be anticipated for patients. Using a genetically engineered mouse model of ARMS, validated for active Igf1r signaling, we show that the prototypic Igf1r inhibitor NVP-AEW541 can inhibit cell growth and induce apoptosis in vitro in association with decreased Akt and Mapk phosphorylation. However, drug resistance in vivo is more common and is accompanied by Igf1r overexpression, Mapk reactivation, and Her2 overexpression. Her2 is found to form heterodimers with Igf1r in resistant primary tumor cell cultures, and stimulation with Igf2 leads to Her2 phosphorylation. The Her2 inhibitor lapatinib cooperates with NVP-AEW541 to reduce Igf1r phosphorylation and to inhibit cell growth even though lapatinib alone has little effect on growth. These results point to the potential therapeutic importance of simultaneous targeting of Igf1r and Her2 to abrogate resistance.

Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group.

BACKGROUND: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children. METHODS: The authors analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants aged < 1 year with nonmetastatic RMS who received multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803. RESULTS: Seventy-six infants with nonmetastatic RMS were treated on the 3 protocols from 1991 to 2005. Their median age was 7.4 months (range, 0.1-12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). A parameningeal primary tumor site was less common in this infant cohort (3%) than in all patients who were treated on IRS-IV (25%). The estimated 5-year failure-free survival and overall survival rates (95% confidence interval [CI]) were 57% (95% CI, 44%-67%) and 76% (95% CI, 65%-85%), respectively, for infants compared with 81% (95% CI, 79%-83%) and 87% (95% CI, 85%-89%), respectively, for children ages 1 to 9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with distant failure (n = 3) or without distant failure (n = 20). The overall local failure rate was 30%. The median time to treatment failure was 13 months. The failure-free survival rate was worse for infants who had IRS Group III tumors and for those who received less than protocol-recommended radiation therapy. CONCLUSIONS: Infants with RMS appeared to have worse outcomes than older patients, in part because of high rates of local failure. The authors concluded that concerns regarding morbidity in infants and reluctance to use aggressive local control measures may lead to higher rates of local failure.

Emergency department presentation of childhood cancer.

Cancer is the second leading cause of death in children in the United States and is the most common cause of death due to disease. Although the signs and symptoms of these patients can be vague and can mimic other more common childhood illnesses, there are often specific elements of the cancer patient's history, examination, and laboratory evaluation that can lead the provider to the correct diagnosis. The manifestations of certain types of cancer constitute medical emergencies that require acute intervention. This article reviews the most common presentations of childhood cancer and the appropriate initial management in the Emergency Department.

Body mass index predicts insulin resistance in survivors of pediatric acute lymphoblastic leukemia.

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapies have been associated with many late effects, including obesity, hyperglycemia, and insulin resistance. Few data are available linking these abnormalities to specific risk factors present during ALL treatment. METHODS: Retrospective cohort study with prospective follow-up. Subjects had been diagnosed with ALL at ages 1-18 years and had been off chemotherapy for >9 months. Oral glucose tolerance testing (OGTT) was performed and these results compared to demographic, treatment, and anthropomorphic data from medical records. RESULTS: Twenty-seven subjects (11 female) were evaluated. Mean (+/-SD) diagnosis age 5.7 +/- 3.5 years, mean study age 11.3 +/- 3.7 years, mean time off therapy 2.8 +/- 1.5 years. Six subjects had transient hyperglycemia during ALL treatment. At study time, one subject had prediabetes; eight (29.6%) had insulin resistance. Insulin resistance was not predicted by glucose levels during treatment, cumulative steroid or asparaginase dose, or type of steroid received. Body mass index (BMI) for age correlated significantly with several measures of insulin resistance, including fasting insulin, HOMA index, Matsuda index and insulin AUC (P = 0.001-0.009). Waist/hip ratio and BMI at ALL diagnosis also correlated with insulin resistance, but these factors' effects could not be separated from BMI at study time. CONCLUSIONS: Variations in ALL therapy and presence of transient hyperglycemia do not appear to increase risk of glucose intolerance or insulin resistance in the first few years after completion of therapy. Elevated BMI strongly predicted insulin resistance in this study, as it does in the general population.

Prevalence of transient hyperglycemia during induction chemotherapy for pediatric acute lymphoblastic leukemia.

BACKGROUND: Transient hyperglycemia (TH) is a recognized side effect of the corticosteroids and asparaginase given during induction chemotherapy for pediatric acute lymphoblastic leukemia (ALL). Information is needed about how TH has been impacted by changes in ALL therapy. This study examined the prevalence of TH in a cohort of pediatric ALL patients and the impact on TH of type of steroid or asparaginase used and of risk factors such as age, gender, and overweight. METHODS: Retrospective record review of patients aged 2-18 years diagnosed with ALL in 1999-2006. TH was defined as >or=2 random glucose values >or=200 mg/dl. Overall prevalence of TH was calculated. Risk factors were evaluated using Chi-square analysis and logistic regression. RESULTS: One hundred sixty-two subjects (70 female) were reviewed, 33 (20.4%) of whom had TH. 42.2% of subjects over age 10 years had TH, compared to 12.0% of younger children (P < 0.001). No gender difference was found. Overweight (BMI >or= 95th percentile) and at risk for overweight (BMI >or= 85th percentile) were significant risk factors for TH (P = 0.007 and P = 0.003, respectively). Native L-asparaginase was associated with increased TH compared to PEG-asparaginase (P = 0.047). There was a non-significant trend toward more TH in patients who received prednisone, but this disappeared in multivariate analysis. CONCLUSIONS: The prevalence of TH in this study was higher than previously reported. Overweight, age >or=10 years, and use of native L-asparaginase were significant predictors of TH.

Outcome after relapse among children with standard-risk acute lymphoblastic leukemia: Children's Oncology Group study CCG-1952.

PURPOSE: The event-free survival (EFS) of children with standard-risk acute lymphoblastic leukemia (SR-ALL) is now more than 80%. However, prognosis after relapse continues to be poor. We examined postrelapse outcomes of children initially treated on the Children's Cancer Group CCG-1952 study. PATIENTS AND METHODS: We evaluated outcomes after bone marrow (BM) relapse and isolated extramedullary (EM) relapse for 347 patients with SR-ALL (WBC < 50,000/microL; age, 1 to 9 years). The prognostic significance of several factors for EFS after relapse (EFS2) was assessed by Cox regression analysis. Stem-cell transplant (SCT) was compared with chemotherapy as salvage treatment. RESULTS: The mean +/- SE times to isolated central nervous system relapse, BM relapse, and isolated testicular relapse were 23 +/- 1 months (range, 1 to 88 months), 36 +/- 1 months (range, 2 to 79 months), and 40 +/- 2 months (range, 16 to 64 months), respectively. The estimated percent +/- SE 3-year EFS2 and overall survival rates after BM relapse were 37% +/- 4% and 46% +/- 4%, respectively, and rates after isolated EM relapse were 57% +/- 5% and 71% +/- 5%, respectively. By multivariate analysis, we found the duration of first remission to be the most significant predictor of EFS2 for either BM relapse or isolated EM relapse. Outcome was equivalent with SCT or chemotherapy after early or late relapse of SR-ALL at any site. CONCLUSION: Duration of first remission remains the most significant predictor of outcome after either BM or isolated EM relapse of SR-ALL. Prognosis after early BM relapse remains poor and is not improved with SCT in this cohort.

Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group.

PURPOSE: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children. PATIENTS AND METHODS: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment. RESULTS: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively. CONCLUSION: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Neuroblastoma found in a 4-year-old after rituximab therapy for opsoclonus-myoclonus.

Opsoclonus-myoclonus, a rare paraneoplastic syndrome that may occur in patients with neuroblastoma, is thought to be a humorally mediated immune reaction to malignant cells that cross-react with autoantigens. This report describes the case of an occult neuroblastoma diagnosed in a 4-year-old female 2 years after presentation of opsoclonus-myoclonus. Although no mass was evident on previous imaging at an interval of 10 months, a computed tomographic scan 4 months after rituximab treatment and 20 months after presentation revealed a new left adrenal mass. Although neuroblastomas can be identified months after presentation of opsoclonus-myoclonus without treatment with rituximab, this report describes one of the longest intervals using up-to-date imaging techniques. Therefore the case raises two concerns: (1) whether the same immune process that causes opsoclonus-myoclonus may suppress neuroblastomas, and (2) whether immunosuppressive therapy with rituximab may inhibit the immune reaction to occult neuroblastomas in patients with unexplained opsoclonus-myoclonus.