ABSTRACT
Severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the promyelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. We report results for six patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. SCN patients should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. For SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.
Subject(s)
Cell Transformation, Neoplastic , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid/therapy , Neutropenia/complications , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Bone Marrow Examination , Child , Child, Preschool , Disease Progression , Female , Hematopoietic Stem Cell Transplantation/mortality , Humans , Infant , Karyotyping , Leukemia, Myeloid/etiology , Male , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/therapy , Neutropenia/congenital , Neutropenia/therapy , Retrospective Studies , Survival Rate , Transplantation Conditioning , Treatment OutcomeABSTRACT
BACKGROUND: Treatment strategies involving dose intensification have recently demonstrated improvements in cure compared with older trials. However, dose-intensive therapy is associated with increased acute and long-term toxicities, particularly in pediatric patients. The Children's Cancer Group initiated this pilot study to assess the feasibility and toxicity of a moderate dose-intensive regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), in children and adolescents with advanced-stage Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Children with stage IIB or IIIB with bulk disease, or stage IV were eligible. Induction consisted of four cycles of escalated dose BEACOPP. The rapidity of response, defined as >70% reduction in disease burden, was assessed after two and four cycles. Rapid responders then received consolidation therapy as per gender-specific guidelines to reduce the risk of gender-specific long-term toxicities of therapy, i.e. females received four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin and vinblastine) without radiation therapy and males received two cycles of ABVD (doxurubicin, bleomycin, vinblastine and dacarbazine) with involved field radiation therapy (IFRT). Slow responders received four cycles of BEACOPP and IFRT. RESULTS: Ninety-nine patients were enrolled. Myelosuppression was frequent. Non-hematological grade 4 toxicities included allergic reaction (two patients), hypotension (one), mucositis (four), infection (three), seizure (one) and elevated transaminases (one). Typhlitis developed in four patients; three recovered and completed dose-modified chemotherapy, while one died of sepsis associated with grade 4 neutropenia. A rapid response was achieved by 45 and 72% of patients after two and four cycles, respectively. There are no disease progressions or secondary malignancies to date. There is only one reported relapse to date. Median follow-up for the cohort is 6 months. CONCLUSIONS: BEACOPP chemotherapy is feasible and generally well tolerated in children with advanced-stage HL. The absence of reported progressive disease and only one relapse to date is encouraging.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/therapeutic use , Cyclophosphamide/therapeutic use , Dacarbazine/therapeutic use , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Hodgkin Disease/drug therapy , Prednisone/therapeutic use , Procarbazine/therapeutic use , Vinblastine/therapeutic use , Vincristine/therapeutic use , Adolescent , Adult , Child , Child, Preschool , Feasibility Studies , Female , Humans , Male , Treatment OutcomeABSTRACT
Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkin's lymphoma (NHL) treated on previous Children's Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol ('Orange') to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass > or = one-third thoracic diameter at T5 and/or LDH > or =2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs. high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 +/- 7% and 80 +/- 7%, respectively. The 5-year EFS and OS were significantly better in the standard- vs. high-risk subgroups (100% vs. 61 +/- 11%) (P < 0.003) and (100% vs. 65 +/- 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) > or =2 x normal (NL) was associated with significantly poorer outcomes (LDH > or =2 x NL vs. <2 x NL) (5-year EFS: 55 +/- 12% vs. 100%) (P < 0.0004). This CCG hybrid regimen, 'Orange', of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 x NL) and Murphy stage III disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Humans , L-Lactate Dehydrogenase/metabolism , Lymphoma, Non-Hodgkin/enzymology , Lymphoma, Non-Hodgkin/pathology , Male , Methotrexate/administration & dosage , Neoplasm Staging , Pilot Projects , Prognosis , Treatment OutcomeABSTRACT
Dendritic cells (DCs) have been shown to be a promising adjuvant for inducing immunity to cancer. We evaluated tumor lysate-pulsed DC in a Phase I trial of pediatric patients with solid tumors. Children with relapsed solid malignancies who had failed standard therapies were eligible. The vaccine used immature DC (CD14-, CD80+, CD86+, CD83-, and HLA-DR+) generated from peripheral blood monocytes in the presence of granulocyte/monocyte colony-stimulating factor and interleukin-4. These DC were then pulsed separately with tumor cell lysates and the immunogenic protein keyhole limpet hemocyanin (KLH) for 24 h and then combined. A total of 1 x 10(6) to 1 x 10(7) DC are administered intradermally every 2 weeks for a total of three vaccinations. Fifteen patients (ages 3-17 years) were enrolled with 10 patients completing all vaccinations. Leukapheresis yields averaged 2.8 x 10(8) peripheral blood mononuclear cells (PBMC)/kg, and DC yields averaged 10.9% of starting PBMC. Patients with neuroblastoma, sarcoma, and renal malignancies were treated without obvious toxicity. Delayed-type hypersensitivity (DTH) response was detected in 7 of 10 patients for KLH and 3 of 6 patients for tumor lysates. Priming of T cells to KLH was seen in 6 of 10 patients and to tumor in 3 of 7 patients as demonstrated by specific IFN-gamma-secreting T cells in unstimulated PBMCs. Significant regression of multiple metastatic sites was seen in 1 patient. Five patients showed stable disease, including 3 who had minimal disease at time of vaccine therapy and remain free of tumor with 16-30 months follow-up. Our results demonstrate that it is feasible to generate large numbers of functional DC from pediatric patients even in those highly pretreated and with a large tumor burden. The DC can be administered in an outpatient setting without any observable toxicity. Most importantly, we have demonstrated the ability of the tumor lysate/KLH-pulsed DC to generate specific T-cell responses and to elicit regression of metastatic disease.
Subject(s)
Dendritic Cells/immunology , Immunotherapy, Adoptive , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/immunology , Adolescent , Child , Child, Preschool , Female , Hemocyanins/immunology , Humans , Hypersensitivity, Delayed/immunology , Interferon-gamma/metabolism , Leukapheresis , Male , T-Lymphocytes/metabolism , VaccinationABSTRACT
Relapsed congenital talipes equinovarus is difficult to assess and treat. Pedobarography provides dynamic measurement of the pressures under the foot, and may be used in the assessment of these patients both before and after operation. Our findings showed a statistically significant difference in the distribution of pressure across the foot after treatment by the Ilizarov technique.
Subject(s)
Clubfoot/surgery , Ilizarov Technique , Adolescent , Child , Child, Preschool , Humans , Postoperative Care , Preoperative Care , Pressure , Prospective StudiesABSTRACT
PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children's Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Health Care Costs , Length of Stay/economics , Outcome Assessment, Health Care/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child , Child, Preschool , Clinical Trials as Topic/statistics & numerical data , Cost-Benefit Analysis , Disease-Free Survival , Drug Administration Schedule , Humans , Outcome Assessment, Health Care/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , RecurrenceABSTRACT
Early death in Schimke immuno-osseous dysplasia often results from renal failure and/or cell-mediated immunodeficiency. Kidney transplants have improved renal function, but effective therapy for the immunodeficiency has not yet been reported. We describe markedly improved marrow function 2 years after bone marrow transplantation in a boy with Schimke immunoosseous dysplasia.
Subject(s)
Bone Marrow Transplantation , Osteochondrodysplasias/genetics , Osteochondrodysplasias/therapy , Antigens, CD/blood , Child , Child, Preschool , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Infant, Newborn , Kidney Transplantation , Lymphopenia/complications , Lymphopenia/diagnosis , Male , Osteochondrodysplasias/complications , Pedigree , Renal Insufficiency/complications , Renal Insufficiency/surgery , Tacrolimus/therapeutic useABSTRACT
PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12-14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12-14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12-14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P =.04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P =.25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P =.72). CONCLUSION: Aberrations of 13q12-14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 13 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Chromosome Breakage , Chromosome Deletion , Clinical Trials as Topic , Cohort Studies , Disease-Free Survival , Humans , Infant , Karyotyping , Ploidies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Treatment OutcomeABSTRACT
Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (<10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC >500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.
Subject(s)
Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Methotrexate/administration & dosage , Tacrolimus/administration & dosage , Tacrolimus/toxicity , Actuarial Analysis , Acute Disease , Adolescent , Child , Child, Preschool , Female , Graft Survival , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/toxicity , Infant , Infections/chemically induced , Liver Failure/chemically induced , Liver Failure/therapy , Magnesium Deficiency/blood , Magnesium Deficiency/chemically induced , Magnesium Deficiency/drug therapy , Male , Methotrexate/toxicity , Survival Rate , Tacrolimus/blood , Time Factors , Transplantation, Homologous , Vascular Diseases/chemically inducedABSTRACT
PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.
Subject(s)
Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 5/genetics , Diploidy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Trisomy/genetics , Child , Child, Preschool , Female , Humans , Infant , Karyotyping , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Predictive Value of Tests , Prognosis , Treatment OutcomeABSTRACT
Between October 1995 and October 1998, 24 children aged 9 months to 17 years (median 11 years) underwent cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) transplantation for treatment of hematological disorders. All of the transplants were the first allogeneic transplant for the recipient. Twenty patients were transplanted for hematological malignancies (ALL = 8, AML = 6, CML = 4, MDS = 2) and four patients were transplanted for non-malignant disease (thalassemia major = 2, Wiskott-Aldrich syndrome = 1, Kostmann's syndrome = 1). Nineteen donors were HLA-identical siblings, four were HLA-matched or single antigen mismatched parents, and one was a syngeneic transplant. Donors aged 8 to 38 years (median 15 years, 14 donors <18 years) received G-CSF 10 microg/kg/day subcutaneously beginning 4 days before PBSC collection and were submitted to one to three leukapheresis collections. The median CD34+ cell yield was 7.8 x 106 cells/kg recipient body weight. All patients achieved an ANC >0.5 x 109/l after a median of 13 days (range 10-21). Twenty-three patients eventually achieved platelet transfusion independence. One patient died on day 63 without ever achieving platelet transfusion independence. Four patients received platelet transfusions to maintain a platelet count well above 20 x 109/l due to bleeding complications. Of the 19 evaluable patients, the median time to a non-transfused platelet count of 20 x 109/l was 12 days (range 0-44). Ten of 23 at-risk patients developed acute GVHD grades II to IV, with grades III to IV in four patients. Twelve of 19 patients followed for at least 100 days have developed chronic GVHD (extensive = 2, limited = 10) with an actuarial risk of chronic GVHD of 75% at 1 year. The Kaplan-Meier estimate of event-free survival is 65% at 2 years. Four patients died (GVHD = 3, VOD = 1), three patients relapsed, and one patient with thalassemia major had a late graft failure with autologous recovery. Based upon our experience, allogeneic PBSCT is safe for both pediatric donors and recipients and engraftment of neutrophils and platelets is rapid. Bone Marrow Transplantation (2000) 25, 13-18.
Subject(s)
Cytokines/pharmacology , Graft vs Host Disease/etiology , Hematologic Diseases/therapy , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation , Adolescent , Child , Child, Preschool , Chronic Disease , Female , Graft Survival , Graft vs Host Disease/physiopathology , Hematologic Diseases/physiopathology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Incidence , Infant , Male , Survival Analysis , Transplantation, HomologousABSTRACT
PURPOSE: To describe patterns of central venous catheter (CVC) use and determine the risk of infection associated with a catheter in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Children with ALL (n = 1934), participating in Children's Cancer Group studies for good-prognosis ALL (CCG-1881) and intermediate-risk ALL (CCG-1891) were evaluated in a retrospective case-control study. The presence of a catheter and the occurrence of infectious complications were recorded after each treatment phase. RESULTS: Young age and enrollment in the intermediate-risk study were associated with higher rates of catheter use. During each of the first four phases of therapy, the adjusted risk of infection was two- to fourfold higher when a catheter was in place. The proportion of patients with infection during the first four phases of therapy was 2.6 times higher with a CVC (14.4% versus 5.7%). Catheter use was associated with significantly increased hospitalization rates during induction, consolidation, and interim maintenance, but not during delayed intensification. A catheter did not significantly increase the risk of fever during neutropenia. CONCLUSION: The presence of a CVC increases the risk of infection during the early phases of low-intensity therapy for ALL.
Subject(s)
Antineoplastic Agents/administration & dosage , Catheterization, Central Venous/adverse effects , Infections/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Case-Control Studies , Child , Child, Preschool , Female , Humans , Incidence , Male , Retrospective Studies , Risk , United StatesABSTRACT
PURPOSE: A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990. PATIENTS AND METHODS: One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease. RESULTS: Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting. CONCLUSION: The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Adolescent , Bleomycin/administration & dosage , Child , Combined Modality Therapy , Dacarbazine/administration & dosage , Doxorubicin/administration & dosage , Female , Hodgkin Disease/pathology , Hodgkin Disease/radiotherapy , Humans , Male , Mechlorethamine/administration & dosage , Multivariate Analysis , Neoplasm Staging , Prednisone/administration & dosage , Procarbazine/administration & dosage , Prognosis , Proportional Hazards Models , Survival Analysis , Vinblastine/administration & dosage , Vincristine/administration & dosageABSTRACT
BACKGROUND: Early response to therapy is defined as the initial response prior to Day 28 of treatment, the conventional time of marrow evaluation. The number of reports linking early response to therapy with the ultimate outcome of childhood acute lymphoblastic leukemia is substantial and growing. When this study began, these experiences had yet to be comprehensively reviewed. METHODS: A comprehensive search of the published literature yielded contributory reports of 14 trials conducted in the United States and Europe. In addition, unpublished data from one Children's Cancer Group trial were made available. Outcome measures were standardized by conversion to ratios of the incidence of adverse events among poorer and better responders. RESULTS: Early response to therapy was an independent prognostic factor in each of the 15 trials, which together included more than 10,000 patients. The incidence of slower early response ranged from 2-33%, with various measures and criteria used in different trials. Patients with a slower early response were 1.5-6.1 times (median, 2.7) more likely to have an adverse event than patients with a more rapid early response, however defined. Early response maintained prognostic significance after the exclusion of induction failure and within risk strata defined by age, white blood cell count, and/or immunophenotype. Its significance was also maintained in multivariate analyses where performed. CONCLUSIONS: Early response to therapy, whether determined by evaluation of bone marrow or peripheral blood, is a consistent, independent prognostic factor in childhood acute lymphoblastic leukemia. Slower early response may serve as a useful surrogate for outcome, a more complex end point, in investigations of the cellular and molecular determinants of resistance to therapy. It may also allow early identification of a patient subpopulation for whom current therapy is less effective and alternative strategies may be justified.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Examination , Child , Clinical Trials as Topic , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: To describe the pharmacokinetic parameters of gentamicin and tobramycin in pediatric bone marrow transplant patients. DESIGN: Retrospective medical record review. SETTING: Pediatric bone marrow transplant unit in a university teaching hospital. MAIN OUTCOME MEASURES: Pharmacokinetic parameters (apparent volume of distribution [Vd] in L/kg, half-life [t1/2] in h, elimination rate constant [ke] in h-1, clearance [Cl] in mL/min/1.73 m2 and mL/min/kg) calculated from serum concentrations. PATIENTS: Thirty-three patients aged 15 years or less who underwent bone marrow transplant and received gentamicin or tobramycin. RESULTS: Mean pharmacokinetic parameters were Vd 0.32 +/- 0.07 L/kg, t1/2 2.32 +/- 0.65 h, Cl 1.71 +/- 0.53 mL/min/kg, and Cl 86.2 +/- 24.5 mL/min/1.73 m2. Factors such as disease state, type of marrow graft, gender, or exposure to cyclosporine had no significant effect on pharmacokinetic parameters. Linear regression indicated a weak relationship between serum creatinine (SCr) and Cl in mL/min/kg (r = 0.59), but no relationship was found between SCr and Cl in mL/min/1.73 m2, between age and apparent Vd, or between SCr and apparent Vd. Models for estimating Cl and Ke developed by multiple regression were somewhat predictive (r = 0.7). Required calculated maintenance dosages to obtain therapeutic concentrations were 8, 7, and 6 mg/kg/d in children 6 or younger, 7-12, and 13-15 years, respectively. CONCLUSIONS: The mean Cl and apparent Vd for all ages are similar to those reported in pediatric oncology patients who had not undergone marrow transplantation. Children 6 years or younger had lower than expected Cls and larger apparent Vds than did the older children. Dosages estimated to be necessary to achieve therapeutic concentrations were 6-8 mg/kg/d.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Bone Marrow Transplantation , Gentamicins/pharmacokinetics , Tobramycin/pharmacokinetics , Adolescent , Anti-Bacterial Agents/blood , Child , Child, Preschool , Female , Gentamicins/blood , Half-Life , Humans , Male , Regression Analysis , Retrospective Studies , Tobramycin/bloodABSTRACT
PURPOSE: Wilms tumor is the most common renal neoplasm in children. The diagnosis is usually suggested by anatomic imaging and established by biopsy or resection. The principal roles of functional imaging have been the search for skeletal metastases and evaluation of renal function. We hypothesized that, like many tumors, Wilms tumors could concentrate 18F-FDG and that evaluation of the metabolic activity of these neoplasms might prove clinically useful. MATERIALS AND METHODS: Three patients with known or suspected Wilms tumors underwent positron emission tomography (PET) with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) scanning (four scans). A patient with a single Wilms tumor was studied once at the time of diagnosis. The two patients with bilateral Wilms tumors were studied during therapy. RESULTS: Uptake of FDG was present in the Wilms tumor studied at diagnosis, and in one of the tumors in each of the patients with bilateral disease studied during therapy. In all three cases, the results of the PET scans influenced therapeutic decisions. CONCLUSION: PET FDG scanning may be useful for the management of selected patients with Wilms tumors.
Subject(s)
Deoxyglucose/analogs & derivatives , Fluorine Radioisotopes , Kidney Neoplasms/diagnostic imaging , Radiopharmaceuticals , Wilms Tumor/diagnostic imaging , Child, Preschool , Female , Fluorodeoxyglucose F18 , Humans , Tomography, Emission-ComputedABSTRACT
A 13-year-old boy who had undergone allogenic bone marrow transplantation for treatment of acute lymphocytic leukemia presented with bilateral periorbital rash and swelling. A CT scan showed bilateral symmetric periorbital swelling, subconjunctival fluid collections, and lacrimal gland enlargement. The patient was initially treated for presumed cellulitis. However, persistently negative regional cultures (eye, nasopharynx), a rapid response to immunosuppressive therapy after several days of nonresponse to intravenous antibiotic therapy, and ultimately, results of a skin biopsy confirmed the diagnosis of acute graft-versus-host disease.
Subject(s)
Graft vs Host Disease/diagnostic imaging , Orbital Diseases/diagnostic imaging , Tomography, X-Ray Computed , Acute Disease , Adolescent , Anti-Bacterial Agents , Biopsy , Bone Marrow Transplantation/adverse effects , Cellulitis/drug therapy , Cellulitis/pathology , Drug Therapy, Combination/administration & dosage , Drug Therapy, Combination/therapeutic use , Edema/pathology , Exudates and Transudates , Graft vs Host Disease/drug therapy , Graft vs Host Disease/pathology , Humans , Immunosuppressive Agents/therapeutic use , Injections, Intravenous , Lacrimal Apparatus Diseases/pathology , Male , Orbital Diseases/drug therapy , Orbital Diseases/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Skin/pathology , Transplantation, Homologous , Urticaria/pathologyABSTRACT
We investigated the report of a community cluster of cancers in 33 children, which included two siblings known to have dominantly inherited Li-Fraumeni syndrome and a germline p53 mutation. After defining criteria for inclusion in the cluster, the 12 eligible childhood cancer probands diagnosed between 1980 and 1989 were not excessive (expected, ten cases). The corresponding childhood cancer mortality rates for the community fluctuated between 1950 and 1989 and were not increased overall. However, three additional probands had family histories of childhood cancer that suggested a forme fruste of Li-Fraumeni syndrome. The epidemiological data suggested a geographic cluster of this rare hereditary disorder, but absence of germline p53 mutation in the three other multicase families indicates genetic heterogeneity. Laboratory studies can assist analyses of suspected clusters, although investigations of geographic clusters of hereditary cancers raise complex issues of confidentiality and protection of affected individuals, their families, and the community.
Subject(s)
Brain Neoplasms/epidemiology , Disease Outbreaks , Li-Fraumeni Syndrome/epidemiology , Rural Health , Sarcoma/epidemiology , Adolescent , Child , Genes, p53/genetics , Germ-Line Mutation , Humans , Li-Fraumeni Syndrome/genetics , Li-Fraumeni Syndrome/mortality , Space-Time Clustering , United States/epidemiologyABSTRACT
The predictive performance of estimating creatinine clearance (CrCl) with pediatric clearance models was evaluated. Thirty-two pediatric patients with stable renal function between the ages of 1 and 14 years about to undergo bone marrow transplantation (BMT) who had 12-24 h urine collections for measurement of CrCl were studied. The measured CrCl was compared to CrCls calculated from seven models used to estimate CrCl in the pediatric population. The models used were Traub and Johnson, Schwartz et al, Counahan et al, modified Counahan et al, Ghazali and Barratt, Shull et al and Dechaux et al. Coefficients of determination (r2) between measured and estimated CrCls from models 1 to 7 were 0.47, 0.47, 0.47, 0.49, 0.47, 0.52, 0.47. The mean absolute percent errors for the models were 23.2-45.2%. In the majority of children, models overestimated CrCl. The tested models did not accurately predict CrCl and did not provide a reliable alternative to measured CrCl.
Subject(s)
Bone Marrow Transplantation , Creatinine/metabolism , Hematologic Neoplasms/complications , Kidney Diseases/diagnosis , Kidney Function Tests , Adolescent , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Female , Hematologic Neoplasms/therapy , Hepatic Veno-Occlusive Disease/complications , Humans , Infant , Kidney Diseases/complications , Kidney Diseases/epidemiology , Male , Metabolic Clearance Rate , Models, Biological , Neoplasms/complications , Neoplasms/therapy , Predictive Value of Tests , Retrospective Studies , RiskABSTRACT
PURPOSE: To assess the uptake in neuroblastoma of 2-[fluorine-18] -fluoro-2-deoxy-D-glucose (FDG) versus metaiodobenzylguanidine (MIBG). MATERIALS AND METHODS: Seventeen patients with known or suspected neuroblastoma underwent FDG positron emission tomography (PET) (20 scans) and MIBG scintigraphy. Tumor uptake of FDG was quantified on positive PET scans. RESULTS: Tumor uptake of FDG was detected in 16 of 17 patients (18 of 20 scans). Neuroblastomas and their metastases avidly concentrated FDG prior to chemotherapy or radiation therapy. Uptake after therapy was variable. Uptake of FDG was intense in one patient with neuroblastoma that failed to accumulate MIBG. In 13 of the 20 scans, however, MIBG was rated superior to FDG for delineation of tumor compared with background and normal organs. CONCLUSION: Most neuroblastomas accumulate FDG. The mechanism of MIBG uptake is more intense prior to therapy. Concentration of FDG is not dependent on type 1 catecholamine uptake. FDG PET helps define the distribution of neuroblastomas that fail to concentrate MIBG.