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Yu A.L.,University of California at San Diego | Yu A.L.,Academia Sinica, Taiwan | Gilman A.L.,Levine Childrens Hospital | Ozkaynak M.F.,New York Medical College | And 18 more authors.
New England Journal of Medicine | Year: 2010

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P = 0.01) and overall survival (86±4% vs. 75±5% at 2 years, P = 0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. Copyright © 2010 Massachusetts Medical Society. All rights reserved.Results:With 61% of the number of expected events observed, the study met the criteria for early stopping of the randomization, on the basis of the superiority of immunotherapy over standard therapy with regard to event-free survival. The 2-year estimate for event-free survival was 66% in the immunotherapy group and 46% in the standard-therapy group. Immunotherapy was also superior to standard therapy with regard to the estimated rate of overall survival (86% vs. 75% at 2 years). The rate of event-free survival was significantly greater in the immunotherapy group than in the standard-therapy group (63% vs. 42% at 2 years). There was also a trend toward improved overall survival with immunotherapy as compared with standard therapy (84% vs. 76% at 2 years). The 2-year estimates for event-free survival and overall survival were 36% (16 events) and 76% (10 deaths, all disease-related), respectively in 25 patients nonrandomly assigned to receive immunotherapy. The event-free survival was worse in patients with disease of INSS stage 4 than in patients with disease of INSS stage 2, 3, or 4S. Diploidy was predictive of worse overall survival than hyperdiploidy. A complete or very good partial response, as compared with a partial response, before autologous stem-cell transplantation was predictive of improved event-free survival and overall survival. The treatment-group comparisons were not influenced by these factors. The effects of most interest reported in the immunotherapy group were pain, hypotension, capillary leak syndrome, and hypersensitivity reactions, with relatively few toxic effects in the standard-therapy group. Pain of grade 3 or 4 was noted in 52% of patients (during 25% of 598 cycles of immunotherapy). Pain reactions in the immunotherapy group were most frequent during cycle 1, occurring in 37% of patients, and decreasing to 14% during cycle 5. The most common site of pain was the abdomen. The capillary leak syndrome was reported in a total of 23% of patients, during 8% of immunotherapy cycles. It occurred more frequently during cycles 2 and 4, which involved Proleukin, with incidences of 11% and 13%, respectively, as compared with 3 to 7% during courses involving GM-CSF (cycles 1, 3, and 5). Grade 3 or 4 hypersensitivity reactions were reported in 25% of patients, during 15% of immunotherapy cycles. Hypersensitivity reactions were more frequent during the two cycles involving Proleukin, with incidences of 26% and 25%, as compared with 5 to 12% during the three cycles involving GM-CSF. Such reactions may be attributable to symptoms and signs that reflect both toxic effects of Proleukin and antibody-related hypersensitivity. Other toxic effects that were common during immunotherapy cycles included fever (39%), hypokalemia (35%), hyponatremia (23%), liver dysfunction (abnormal alanine aminotransferase level, 23%), hypotension (18%), diarrhea (13%), urticaria (13%), and hypoxia (13%). Early in the study, 2 patients were inadvertently given an overdose of the scheduled Proleukin due to a medication error; one of these patients died of Proleukin-related capillary leak and pulmonary edema. All other toxic effects were self-limited and resolved soon after the cessation of treatment and well before the beginning of the subsequent treatment.Patients:226 patients. Standard-therapy group (isotretinoin only): n=113, 4 were <18 months and 109 were ≥18 months. Immunotherapy group (6 cycles of isotretinoin and 5 concomitant cycles of ch14.18 in combination with alternating GM-CSF and Proleukin): n=113, 4 were <18 months and 109 were ≥18 months; 6 did not receive assigned intervention, having declined immunotherapy and received standard therapy. 25 patients (over 18 months of age) were nonrandomly assigned to receive immunotherapy because of biopsy-proven residual disease after autologous stem-cell transplantation. Follow-up: 4 days to 6.9 years (median 2.1 years). Dropouts: n=40 [23 on immunotherapy (17 due to side effects) and 17 on standard therapy].Indications:132 patients with refractory neuroblastoma [International Neuroblastoma Staging System stage (INSS): 2 (n=4), 3 (n=10), 4S (n=2), 4 (n=89) and unknown (n=8)].TypeofStudy:An open, randomized study evaluating whether adding Proleukin or granulocyte-macrophage colony-stimulating factor (GM-CSF) with monoclonal antibody ch14.18 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. NCT00026312.DosageDuration:3.0×106 IU per square meter daily was given in cycles 2 and 4 by means of continuous infusion, for 4 days during week 1, for 4 days during week 2 at 4.5×106 IU per square meter daily. Duration: 2 years. 2 patients were inadvertently given an overdose of the scheduled Proleukin (i.e., a dose >20 times the scheduled dose) due to a medication error.AdverseEffects:An unspecified number of patients had neuropathic pain, hypotension, hypoxia, fever without neutropenia, urticaria, infection (any), infection (catheter related), nausea, vomiting, diarrhea, hyponatremia, hypokalemia, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, hypercalcemia, serum sickness, seizure, central nervous system cortical symptoms (encephalopathy, confusion and psychosis). 12 (11%) patients in cycle 2 and 15 (13%) in cycle 4 had capillary leak syndrome; 29 (26%) and 28 (25%), respectively hypersensitivity reactions. 1 patient had drug intoxication characterized by capillary leak and pulmonary edema. 17 patients had adverse events leading to withdrawal.FreeText:Primary endpoint: event-free survival. Secondary endpoint: overall survival. Tumor MYCN status: 52 were not amplified, 36 amplified and 25 unknown. Tumor histologic features: 4 were favorable, 68 unfavorable and 41 unknown. Tumor ploidy: 49 were hyperdiploid, 35 diploid and 29 unknown. 28 patients had ≥1 purged stem cell infusions. Response before autologous stem cell transplantation (ASCT): 40 complete response, 47 very good partial response and 26 partial response. 107 patients had 1 ASCT and 6 had 2 ASCTs. In nonrandomized patients, 23 had INSS stage 4 disease; 6 tumors showed MYCN amplification, 16 had unfavorable histologic features, 12 were diploid, 21 had a partial response before ASCT and only 1 had undergone 2 autologous stem-cell transplantations. Patients had induction therapy, ASCT, and radiotherapy. The monoclonal antibody ch14.18 was given in cycles 1 through 5; GM-CSF was given in cycles 1, 3, and 5; and isotretinoin was given during the last 2 weeks in each of the five cycles and also given by itself during a final 6th cycle. Concomitant drugs: isotretinoin at a dose of 160 mg per square meter daily, monoclonal antibody ch14.18 at a dose of 25 mg per square meter daily for 4 consecutive days.AuthorsConclusions:In summary, the addition of ch14.18, GM-CSF, and interleukin-2 to isotretinoin therapy was associated with improved event-free and overall survival among children with high-risk neuroblastoma who had a response to initial chemotherapy and received immunotherapy within 100 days after autologous stem-cell transplantation. Our data suggest that more routine use of this immunotherapy regimen for such patients may be beneficial. Future avenues of investigation include developing more effective and less toxic ways to stimulate ch14.18-mediated antibody-dependent cell-mediated cytotoxicity and identifying more efficacious GD2-targeted monoclonal antibodies or genetically modified constructs targeting GD2.

Rodenbach K.E.,University of Rochester | Furth S.L.,Childrens Hospital of Philadelphia | Moxey-Mims M.M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Mitsnefes M.M.,Cincinnati Childrens Hospital Medical Center | And 3 more authors.
American Journal of Kidney Diseases | Year: 2015

Background Hyperuricemia is associated with essential hypertension in children. No previous studies have evaluated the effect of hyperuricemia on progression of chronic kidney disease (CKD) in children. Study Design Prospective observational cohort study. Setting & Participants Children and adolescents (n = 678 cross-sectional; n = 627 longitudinal) with a median age of 12.3 (IQR, 8.6-15.6) years enrolled at 52 North American sites of the CKiD (CKD in Children) Study. Predictor Serum uric acid level (<5.5, 5.5-7.5, and >7.5 mg/dL). Outcomes Composite end point of either >30% decline in glomerular filtration rate (GFR) or initiation of renal replacement therapy. Measurements Age, sex, race, blood pressure status, GFR, CKD cause, urine protein-creatinine ratio (<0.5, 0.5-<2.0, and ≥2.0 mg/mg), age- and sex-specific body mass index > 95th percentile, use of diuretics, and serum uric acid level. Results Older age, male sex, lower GFR, and body mass index > 95th percentile were associated with higher uric acid levels. 162, 294, and 171 participants had initial uric acid levels < 5.5, 5.5 to 7.5, or >7.5 mg/dL, respectively. We observed 225 instances of the composite end point over 5 years. In a multivariable parametric time-to-event analysis, compared with participants with initial uric acid levels < 5.5 mg/dL, those with uric acid levels of 5.5 to 7.5 or >7.5 mg/dL had 17% shorter (relative time, 0.83; 95% CI, 0.62-1.11) or 38% shorter (relative time, 0.62; 95% CI, 0.45-0.85) times to event, respectively. Hypertension, lower GFR, glomerular CKD cause, and elevated urine protein-creatinine ratio were also associated with faster times to the composite end point. Limitations The study lacked sufficient data to examine how use of specific medications might influence serum uric acid levels and CKD progression. Conclusions Hyperuricemia is a previously undescribed independent risk factor for faster progression of CKD in children and adolescents. It is possible that treatment of children and adolescents with CKD with urate-lowering therapy could slow disease progression. © 2015 National Kidney Foundation, Inc.

Gripp K.W.,DuPont Company | Demmer L.A.,Levine Childrens Hospital
American Journal of Medical Genetics, Part A | Year: 2013

Keratoconus is a corneal dystrophy with progressive corneal thinning resulting in abnormal corneal shape and astigmatism. Corneal hydrops and rupture can occur and corneal transplant may become necessary. While keratoconus is rare in the general population occurring in about 1/2,000 individuals, it is more common in individuals with intellectual disability and syndromic conditions. Connective tissue abnormalities, most typically brittle cornea syndrome, have frequently been reported in association with keratoconus. Here, we report on bilateral keratoconus with acute hydrops in the left eye of a 24-year-old male with Costello syndrome. The patient was treated medically. After resolution of the hydrops, he had significant visual impairment from the resulting irregular astigmatism and scarring. This is the second report of keratoconus in Costello syndrome, suggesting an increased risk for this corneal dystrophy in individuals with Costello syndrome. Ongoing ophthalmological surveillance may be necessary for adult individuals with Costello syndrome, and apparent vision changes should be evaluated expediently. © 2012 Wiley Periodicals, Inc.

Sparks S.E.,Levine Childrens Hospital
North Carolina medical journal | Year: 2013

Since phenylketonuria was first screened for in the 1960s, newborn screening has expanded to include more than 30 conditions. This commentary provides an update on newborn screening, including the follow-up of abnormal findings, the limitations of such screening, and the ethical questions that screening raises.

Alvarado D.M.,University of Washington | Buchan J.G.,University of Washington | Frick S.L.,Levine Childrens Hospital | Herzenberg J.E.,Sinai Hospital | And 2 more authors.
European Journal of Human Genetics | Year: 2013

Talipes equinovarus is one of the most common congenital musculoskeletal anomalies and has a worldwide incidence of 1 in 1000 births. A genetic predisposition to talipes equinovarus is evidenced by the high concordance rate in twin studies and the increased risk to first-degree relatives. Despite the frequency of isolated talipes equinovarus and the strong evidence of a genetic basis for the disorder, few causative genes have been identified. To identify rare and/or recurrent copy number variants, we performed a genome-wide screen for deletions and duplications in 413 isolated talipes equinovarus patients using the Affymetrix 6.0 array. Segregation analysis within families and gene expression in mouse E12.5 limb buds were used to determine the significance of copy number variants. We identified 74 rare, gene-containing copy number variants that were present in talipes equinovarus probands and not present in 759 controls or in the Database of Genomic Variants. The overall frequency of copy number variants was similar between talipes equinovarus patients compared with controls. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a major role for recurrent copy number variations in the etiology of isolated talipes equinovarus, they do suggest a role for genes involved in early embryonic patterning in some families that can now be tested with large-scale sequencing methods. © 2013 Macmillan Publishers Limited All rights reserved.

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