Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases.

BACKGROUND: Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH. OBJECTIVES: The objective of this study was to perform a meta-analysis of published cases of nHLH. METHODS: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case. RESULTS: A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6-27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time. CONCLUSIONS: Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

Urine Methotrexate Concentration at 46-48 Hours Post-Treatment Reflects Methotrexate-Induced Acute Kidney Injury.

Early identification of methotrexate-induced acute kidney injury (AKI) and delayed elimination of methotrexate are critical to limiting toxicity of the drug. The current monitoring strategy consists of serial serum methotrexate concentrations at 24, 36, 42, and 48 hours. Appropriate serum concentration monitoring and intervention does not always prevent AKI. Therefore, ongoing study of biomarkers and improved methods of screening for methotrexate-induced AKI is critical to reduce toxicity. This case series reports urine methotrexate values of 4 patients undergoing treatment with high-dose methotrexate. Urine methotrexate concentration was measured 46 to 48 hours after methotrexate infusion. Urine methotrexate concentration was compared with the duration of drug clearance from the serum. Only 1 patient (case 3) developed AKI. Serum concentration of methotrexate were < 0.3 µmol/L at 42, 48, and 48 hours in patients 1, 2, and 4, respectively, and at 168 hours in patient 3 (p < 0.01). Urine methotrexate concentrations were 2.77, 6.45, and 7.8 (µmol/L), in patients 1, 2, and 4, respectively, and 113.69 (µmol/L) in patient 3 (p < 0.001). This case series provides preliminary data that urine methotrexate concentration at hours 46 to 48 may reflect AKI. Future studies should investigate the ability of serial urine methotrexate concentrations to predict delayed drug clearance and the development of AKI.

A Validation Study of the Alcohol Related Neurodevelopmental Disorders Behavioral Checklist.

BACKGROUND: The initial confirmatory factor analysis of the Alcohol Related Neurodevelopmental Disorder Behavioral Checklist (ABC) utilized a population of 203 children. The analysis identified 10 independent measures (executive functioning, attention and concentration, cognition, memory, confabulation, gullibility, communication skills, academic skills, living/social skills, and juvenile justice). The 10 measures differentiated children with FASD from non-FASD controls. In this study, we present a validity study of the ABC using a different population of children with FASD and non-FASD controls. METHODS: A chart review identified 224 children with ABC checklist scores who had been evaluated for FASD. From this sample, we implemented a case-control study of 76 children diagnosed with FASD and 76 non-FASD controls who were matched by gender and closest age in years (mean age was 8.5 years). RESULTS: The averages of the total score and individual domain scores were compared between the 2 data sets and then between children with FASD and non-FASD controls. Children with FASD had significantly higher scores on all 10 measures than the non-FASD controls. There were very high sensitivity and specificity scores for the total score cutoff and for all 10 of the individual measures. CONCLUSIONS: In an independent sample, we found minimal differences between the previous data and the current validation study on measures of average total score cutoffs, scores for the 10 measures and correlations. Combining the 2 samples yielded robust differences in scores between children with FASD and non-FASD controls. The sensitivity, specificity and accuracy estimates were also very high. The ABC Screen appears to have acceptable epidemiologic performance data to support its use as a screening tool and as an initial step in differentiating children with FASD from those who do not have FASD.

Phase I trial of low-dose interleukin 2 therapy in patients with Wiskott-Aldrich syndrome.

BACKGROUND: Low dose IL-2 can restore the function of T and NK cells from Wiskott-Aldrich (WAS) patients. However, the safety of in vivo IL-2 in WAS is unknown. OBJECTIVES: A phase-I study to assess safety of low dose IL-2 in WAS. METHODS: Patients received 5 daily subcutaneous IL-2 injections, every 2months, for three courses. A "3+3" dose escalation method was used. RESULTS: 6 patients received the 0.5millionunits/m2/day dose without serious adverse events. However, 2 of 3 patients receiving the 1millionunits/m2/day dose developed thrombocytopenia requiring platelet transfusions. A statistically significant platelet increase occurred in patients receiving the 0.5millionunits/m2/day dose. A trend toward higher T, B and NK cell numbers and higher T regulatory cell percentages was observed. CONCLUSION: We have identified a safe IL-2 dose for WAS patients. Additional trials are indicated to study the efficacy of this immunostimulant as a therapy for WAS.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

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 Children's 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.

Fetal alcohol spectrum disorders and childhood cancer: a concise review of case reports and future research considerations.

We reviewed the published literature on the relationship between childhood cancer and fetal alcohol spectrum disorders (FASD). A Pub Med search identified 12 subjects with the co-occurrence of FASD and cancer. We included an additional case from the author's institution. Neuroblastomas comprised 6 of the 13 (46%) case reports, yet neuroblastomas comprise only about 10% of childhood cancers (z = 4.1; P < 0.001). Other than rhabdomyosarcoma, no other cancer was reported more than once. Few cases of childhood cancer associated with FASD were identified likely due to under ascertainment of FASD.

Prevalence of iron overload in pediatric oncology patients after blood transfusion.

BACKGROUND: Studies evaluating the prevalence of iron overload and its relationship to blood transfusion in pediatric oncology patients are limited. METHODS: Medical records of all pediatric oncology patients treated at Roger Maris Cancer Center (Fargo, North Dakota) were screened. Subjects with measurements of serum ferritin levels after completion of therapy (N=52) were further evaluated. RESULTS: Of the total study population, 37 patients (71.2%) underwent red blood cell (RBC) transfusion and 15 patients (28.8%) did not. Among the transfused patients, 20 patients (54%) had elevated serum ferritin values greater than 250 ng/mL. Among the patients who did not undergo blood transfusion, only 1 patient (6.6%) had an elevated serum ferritin value (P<.01; Fischer exact test). None of the nontransfused patients had ferritin levels greater than 501 ng/mL. CONCLUSION: This study demonstrated that ferritin levels were more likely to be elevated in transfused patients than nontransfused patients. The number of subjects in this study was limited, and further prospective studies are needed.

Pelvic pseudotumor and pseudoaneurysm in a pediatric patient with moderate hemophilia B: successful management with arterial embolization and surgical excision.

Development of pseudotumors is an unusual complication of hemophilia. Treatment is controversial, especially in patients with large proximal lesions. Surgery, while curative, can be associated with massive intra-operative bleeding, infection and amputation. Arterial embolization of blood vessels supplying the pseudotumor may reduce these complications. Herein, we report a 14-year-old patient with moderate hemophilia B with a pelvic pseudotumor and pseudoaneurysm that failed conservative management with factor replacement alone. He was successfully treated with Bead Block and coil embolization followed by surgical extirpation of the lesion 24 hr later.

Pharmacokinetics and tissue distribution of liposomal etoposide in rats.

Precipitation of etoposide and adverse events associated with the co-solvents in intravenous solutions can be avoided by using liposomal etoposide (LE). The pharmacokinetics and distribution of the commercial formulation (ETPI) and LE were compared in rats. The pharmacokinetic profiles were biphasic and similar in the initial phase (C(max), Vd, and t(1/2alpha)). However, LE showed a 60% increase in AUC with a 35% decrease in clearance (p < 0.05). This decreased clearance resulted in a 70% increase in the MRT of etoposide. The uptake of etoposide from LE was higher in macrophage-phagocytic endowed tissues indicating that LE is superior to ETPI for targeted delivery of etoposide.

Central neurocytoma responsive to topotecan, ifosfamide, carboplatin.

A 5-year-old male presented with spinal cord drop metastasis from a recurrent neurocytoma. Topotecan (0.5 mg/m(2)) and carboplatin (250 mg/m(2)) were administered on days 1-3 and ifosfamide (1,800 mg/m(2)) on days 1-5, every 21 days, for three cycles and resulted in complete response without severe complications. A literature review yielded 20 patients with central neurocytoma but no complete responses. The complete response of central neurocytoma to chemotherapy only reported here should be helpful to those caring for patients with this rare tumor.

Response of metastatic recurrent neuroblastoma to nitisinone: a modulator of tyrosine metabolism.

Nitisinone blocks the tyrosine pathway and may be effective in treating neuroblastoma. A 33-month-old male with heavily treated metastatic, recurrent, N-MYC amplified neuroblastoma received nitsinone (0.8 mg/kg/day escalated to 5.0 mg/kg/day). Dramatic tumor regression and resolution of pain without toxicity were observed. At 10 weeks, the tumor progressed. Nitisinone, low dose cyclophosphamide and doxorubicin subsequently produced a very good partial response. At 18 months the disease progressed. The child succumbed 21 months after starting nitisinone. Nitisinone produced an increase in tyrosine and catecholamine metabolite (HVA, VMA, and metanephrines) levels. Nitisinone may be a promising agent in metastatic neuroblastoma.

Successful treatment of doxorubicin and cisplatin resistant hepatoblastoma in a child with Beckwith-Wiedemann syndrome with high dose acetaminophen and N-acetylcysteine rescue.

High dose acetaminophen (HDAC) with N-acetylcysteine (NAC) has been effective in adults with advanced malignancies. We report HDAC with NAC in a child with progressive hepatoblastoma, confirmed at biopsy of an unresectable hepatic mass. Alpha-fetoprotein (AFP) increased despite four courses of doxorubicin and one course of cisplatin, 5-flurouracil, and vincristine. Following HDAC with NAC, AFP markedly decreased. A continued response without toxicity was observed during four subsequent courses of HDAC with NAC and cisplatin. The residual necrotic tumor was resected. The child is now over 8 years disease free. HDAC and NAC are effective and well tolerated for progressive hepatoblastoma.

Ablation of hemophilic FVIII inhibitors with FVIII priming, cyclophosphamide immune suppression, and rapid tapering of FVIII immune tolerance.

The efficacy and toxicity of factor VIII (FVIII) priming, cyclophosphamide immune suppression, and rapid tapering of concurrent FVIII immune tolerance for subjects with hemophilic inhibitors were evaluated. Four subjects with hemophilic inhibitors were studied. Before treatment, inhibitors were present for a median of 8 months (mean 13 +/- 14.0 months). The median FVIII inhibitor titer was 16 BU/mL (mean 27.2 +/- 29.2 BU/mL). Following FVIII priming (80.0 +/- 70.2 U/kg), subjects received cyclophosphamide 1,418 +/- 636 mg/M2 i.v. q3 weeks for 4.4 +/- 1.7 courses. Subjects concurrently received a low (6 U/kg/day), moderate (30 U/kg/day), or high (100 U/kg/day) dose of FVIII followed by a rapid taper as the inhibitor titer decreased or resolved. During treatment, the inhibitor titer initially increased but then rapidly declined. Inhibitors resolved in 3.9 +/- 2.9 months. One inhibitor recurred at 2.8 years, but it was successfully re-treated. Effectiveness did not depend on the FVIII dose. Toxicity was minimal. Cyclophosphamide (1,400 mg/M2) administered after a priming dose of FVIII (80 U/kg) i.v. q3 weeks for 2-6 cycles with a rapid taper of concurrently administered daily FVIII as the inhibitor titer falls is an effective approach to hemophilic inhibitor ablation.

Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival.

In Children's Cancer Group (CCG) study 2891, patients who were recently diagnosed with acute myelocytic leukemia (AML) were assigned randomly to standard- or intensive-timing induction chemotherapy. Patients in first complete remission (CR1) and who had a human leukocyte antigen (HLA)-identical, related donor or a donor disparate at a single class I or II locus were nonrandomly assigned to receive a bone marrow transplant (BMT) by using oral busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). Methotrexate only was given for graft-versus-host disease (GVHD) prophylaxis. One hundred fifty patients received transplants. Grade 3 or 4 acute GVHD occurred in 9% of patients. Patients younger than 10 years had a lower incidence of grade 3 or 4 GVHD (4.6%) compared with patients 10 years or older (17.4%) (P =.044). Disease-free survival (DFS) at 6 years was 67% and 42% for recipients of intensive- and standard-timing induction therapies, respectively. Multivariate analysis showed that receiving intensive-timing induction therapy (P =.027) and having no hepatomegaly at diagnosis (P =.009) was associated with favorable DFS, and grades 3 and 4 acute GVHD were associated with inferior DFS. Multivariate analysis showed that grades 1 or 2 GVHD (P =.008) and no hepatomegaly at diagnosis (P =.014) were associated with improved relapse-free survival (RFS). Our results show that children older than 10 years are at higher risk for developing severe GVHD; acute GVHD is associated with favorable RFS.

Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group.

OBJECTIVES: To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). METHODS: Among 1,832 patients entered on Children's Cancer Group's chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group 1 (n=109) with EML involving skin (with or without other sites of EML), group 2 (n=90) with EML in sites other than skin, and group 3 (n=1,633) without EML. RESULTS: The incidence of EML was 10.9%. Group 1 patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group 1 the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. CONCLUSIONS: Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome.

Impact of smoking on cancer stage at diagnosis.

BACKGROUND: Studies evaluating the relationship between smoking and cancer spread are limited. METHODS: We studied the relationship between cancer stage at diagnosis (local, regional, or metastatic) and smoking history (current, previous, or nonsmoker). For lung cancer, patterns of spread were also studied. RESULTS: In a tumor registry for eastern North Dakota, northwestern Minnesota, and northern South Dakota, 11,716 cases were identified from 1986 to 2001. Current smokers (relative risk [RR], 2.11; 95% confidence interval, 1.93 to 2.32; P <.001) and previous smokers (RR, 1.56; 95% confidence interval, 1.42 to 1.72; P <.001) had an increased risk of metastatic disease at diagnosis. Current smokers (RR, 1.39; 95% confidence interval, 1.29 to 1.51; P <.001), but not previous smokers, also had an increased risk of regional disease. An increase in metastatic disease was most evident for prostate cancer (RR, 1.53; P =.003). An increase in regional disease was most evident for head and neck (RR, 3.53; P <.001), prostate (RR, 1.83; P =.030), and breast cancer (RR, 1.22; P =.005). Compared with previous smokers, current smokers with metastatic lung cancer were more likely to have involvement of the brain (33.6% v 23.0%; P =.004), bone marrow, adrenal gland, and pericardium (24.7% v 15.9%; P =.004). CONCLUSION: Previous or current smoking is a risk factor for increased cancer stage in a wide range of malignancies. Further study is required to determine whether this association is causal.

Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF) administered during acute myelogenous leukemia (AML) induction affects hematopoietic and nonhematopoietic toxicity, length and outcome of induction therapy, event-free survival, overall survival, and prognostic significance of the day 7 bone marrow. PATIENTS AND METHODS: In Children's Cancer Group study 2891, patients were given intensively timed induction with G-CSF (n = 254) after accrual for the regimen without G-CSF (n = 258) was met. RESULTS: Time to neutropenic recovery after induction courses 1 and 2 was significantly shorter for patients who received G-CSF. Times to platelet recovery were similar regardless of G-CSF use. Effects on incidence of grades 3 and 4 toxicities, infections, or fatal infections were not observed. Use of G-CSF reduced the median length of induction by 9 days and hospital stay by 6 days. Induction remission rates, overall survival, and event-free survival were similar with and without G-CSF. Day 7 bone marrow was prognostic of better long-term outcome. Patients with hypercellular day 7 marrow who received G-CSF had a higher remission rate and event-free survival than patients who did not receive G-CSF. CONCLUSIONS: The incidence of severe toxic event and infection, induction remission rate, overall survival, and event-free survival were comparable regardless of G-CSF use. Use of G-CSF decreased neutropenia duration, hospital stay, and length of induction. Patients with hypercellular day 7 bone marrow who received G-CSF had an induction remission rate and event-free survival superior to those of patients who did not receive G-CSF.