Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta.

PURPOSE: Osteogenesis imperfecta (OI) predisposes to recurrent fractures. Patients with the moderate to severe forms of OI present with antenatal fractures, and the mode of delivery that would be safest for the fetus is not known. METHODS: We conducted systematic analyses of the largest cohort of individuals with OI (n = 540) enrolled to date in the OI Linked Clinical Research Centers. Self-reported at-birth fracture rates were compared among individuals with OI types I, III, and IV. Multivariate analyses utilizing backward-elimination logistic regression model building were performed to assess the effect of multiple covariates, including method of delivery, on fracture-related outcomes. RESULTS: When accounting for other covariates, at-birth fracture rates did not differ based on whether delivery was by vaginal route or by cesarean delivery (CD). Increased birth weight conferred higher risk for fractures irrespective of the delivery method. In utero fracture, maternal history of OI, and breech presentation were strong predictors for choosing CD. CONCLUSION: Our study, the largest to analyze the effect of various factors on at-birth fracture rates in OI, shows that CD is not associated with decreased fracture rate. With the limitation that the fracture data were self-reported in this cohort, these results suggest that CD should be performed only for other maternal or fetal indications, not for the sole purpose of fracture prevention in OI.Genet Med 18 6, 570-576.

A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers.

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

Prevalence of obesity was related to HLA-DQ in 2-4-year-old children at genetic risk for type 1 diabetes.

OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.

Next-generation sequencing for viruses in children with rapid-onset type 1 diabetes.

AIMS/HYPOTHESIS: Viruses are candidate causative agents in the pathogenesis of autoimmune (type 1) diabetes. We hypothesised that children with a rapid onset of type 1 diabetes may have been exposed to such agents shortly before the initiation of islet autoimmunity, possibly at high dose, and thus study of these children could help identify viruses involved in the development of autoimmune diabetes. METHODS: We used next-generation sequencing to search for viruses in plasma samples and examined the history of infection and fever in children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study who progressed to type 1 diabetes within 6 months from the appearance of islet autoimmunity, and in matched islet-autoantibody-negative controls. RESULTS: Viruses were not detected more frequently in plasma from rapid-onset patients than in controls during the period surrounding seroconversion. In addition, infection histories were found to be similar between children with rapid-onset diabetes and control children, although episodes of fever were reported less frequently in children with rapid-onset diabetes. CONCLUSIONS/INTERPRETATION: These findings do not support the presence of viraemia around the time of seroconversion in young children with rapid-onset type 1 diabetes.

Pruritic acquired nevus of Ota.

Nevus of Ota is a unilateral, asymptomatic cutaneous and mucosal hyperpigmentation of the face that is congenital or may appear during childhood. We present a case of symptomatic acquired nevus of Ota in an adult, associated with intense pruritus, not described in the literature so far. A 32-year-old woman presented with brownish mottled macules which appeared on her face progressively over 8 days, following the distribution of the first and second divisions of the left trigeminal nerve and partially covering the iris and sclera of the left eye. She reported an intense pruritus in this area. We performed a biopsy on the left forehead, which confirmed the diagnosis of nevus of Ota. Specific stains and immunohistochemistry revealed increased numbers of mast cells. Ophthalmological tests showed acute acquired melanocytosis of the left iris and sclera. The origin of the nevus is still unclear. Several hypotheses suggest a reactivation of melanocytes during their migration from the neural crest. The pruritus reported in our patient may be explained by the increased quantity of mast cells observed in the lesion and/or neuronal stimulation of the ophthalmic and maxillary divisions of the fifth cranial nerve.

The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up.

AIMS/HYPOTHESIS: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes. METHODS: The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study's Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow's milk were compared. RESULTS: TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017. CONCLUSIONS/INTERPRETATION: The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777 FUNDING: The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme 'Quality of Life and Management of Living Resources', contract number QLK1-2002-00372 'Diabetes Prevention'. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation).

Metabolic tests to determine risk for type 1 diabetes in clinical trials.

AIMS: Evaluate the reproducibility and relationship of various metabolic tests conducted as part of the Diabetes Prevention Trial-type 1 diabetes. METHODS: Coefficients of variation, intraclass correlation coefficients, and Pearson correlations between the same metabolic tests performed at different times as well as the different tests were determined. RESULTS: Fasting samples on the same day had a coefficient of variation of < 10 for C-peptide, 11 for insulin, and 2 for glucose. Testing on separate days approximately doubled the variance. Stimulated insulin values had less variance than fasting values and there was only a moderate correlation between fasting and stimulated values on each test. While highly correlated, C-peptide values from mixed meal tolerance tests are significantly lower than that obtained during oral glucose tolerance tests (OGTTs). Neither peak nor area under the curve C-peptide on the oral glucose tolerance test was different between those with abnormal and normal glucose tolerance. Those with abnormal as compared with normal glucose tolerance had lower 30-min C-peptide and a longer time to peak C-peptide. CONCLUSIONS: A large, multi-centre trial, with tests performed over a decade-long period, can provide robust data. C-peptide data from oral glucose tolerance tests and mixed meal tolerance tests differ; therefore, the same stimulation test should be used to evaluate changes in beta cell function over time. Worsening glucose tolerance is associated with lower C-peptide at 30 min and a delay in peak secretion on the oral glucose tolerance test. This Diabetes Prevention Trial-type 1 diabetes data can be used in planning parameters for future studies, including evaluation of new algorithms to determine risk of disease.

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

Redistribution of intracellular Ca2+ stores during phagocytosis in human neutrophils.

Subcellular gradients of cytosolic free Ca2+ concentration, [Ca2+]i, are thought to be critical for the localization of functional responses within a cell. A potential but previously unexplored mechanism for the generation of gradients of [Ca2+]i is the accumulation of Ca2+ stores at the site of Ca2+ action. The distribution of the Ca2+ store markers Ca(2+)-dependent adenosine triphosphatase and calreticulin was investigated in resting and phagocytosing human neutrophils. Both proteins showed an evenly distributed fine granular pattern in nonphagocytosing cells, but became markedly concentrated in the filamentous actin-rich cytoplasmic area around the ingested particle during phagocytosis. This redistribution began at early stages of phagocytosis and did not depend on an increase in [Ca2+]i. Thus, accumulation of Ca2+ stores in a restricted area of the cell may contribute to the generation of localized increases in [Ca2+]i.

Association of class II human histocompatibility leukocyte antigens with rheumatic fever.

The association of class I and II HLA antigens with rheumatic fever and its manifestations was examined in 72 patients, including 48 blacks and 24 Caucasians. No significant association was found between class I antigens and rheumatic fever. In contrast, HLA-DR2 and HLA-DR4 phenotypes were encountered in a significantly higher frequency in black and Caucasian patients with rheumatic fever, respectively, compared with the control populations (P less than 0.005). The most significant association (P less than 0.005) of these DR antigens with a major manifestation of rheumatic fever was found for mitral insufficiency. In addition, a significant association was encountered between persistent elevation of antibody to the group A streptococcal carbohydrate and HLA-DR4 in Caucasian patients (P less than 0.04) or HLA-DR2 in the black patients (P less than 0.001). The frequency of HLA-DR2/4 heterozygotes among patients with rheumatic fever did not differ significantly from controls. These findings support the concept of a genetically determined susceptibility to rheumatic fever and, particularly, to rheumatic heart disease. The association of the clinical manifestations of rheumatic fever and the immune hyperresponsiveness to a streptococcal antigen could be ascribed to a disease-associated immune-response gene which is in linkage disequilibrium with the DR2 and DR4 alleles of HLA-DR locus on chromosome six.

Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription.

We reported previously that daily injections of isophane insulin prevented both hyperglycemia and insulitis in nonobese diabetic (NOD) mice (Atkinson, M., N. Maclaren; and R. Luchetta. 1990. Diabetes. 39:933-937). The possible mechanisms responsible include reduced immunogenicity of pancreatic beta-cells from "beta-cell rest" and induced active immunoregulation to insulin (Aaen, IK., J. Rygaard, K. Josefsen, H. Petersen, C. H. Brogren, T. Horn, and K. Buschard. 1990. Diabetes. 39:697-701). We report here that intermittent immunizations with insulin or its metabolically inactive B-chain in incomplete Freund's adjuvant also prevent diabetes in NOD mice, whereas immunizations with A-chain insulin or with BSA do not. Adoptive transfer of splenocytes from B-chain insulin-immunized mice prevented diabetes in recipients co-infused with diabetogenic spleen cells, an effect that was abolished by prior in vivo elimination of either CD4+ or CD8+ cells. Insulin immunization did not reduce the extent of intraislet inflammation (insulitis); however, it did abolish expression of IFN-gamma mRNA within the insulitis lesions. Immunizations with insulin thus induce an active suppressive response to determinants on the B-chain that converts the insulitis lesion from one that is destructive to one that is protective.

Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives.

Islet cell antibodies (ICA) in the sera of nondiabetic relatives of patients with insulin-dependent diabetes (IDD) are predictive of the disease, a finding that permits the design of intervention strategies to prevent it. However, 85% or more of patients with new onset IDD have no affected relative. We therefore screened 9,696 schoolchildren between the ages of 5 and 18 yr (mean age 10.7 yr) in Pasco County, Florida for ICA in three surveys during 1984/5, 1987/8, and 1990/1 and have followed them prospectively. Approximately 4,000 of these children have been followed for nearly 8 yr. ICA titers > or = 10 Juvenile Diabetes Foundation units on replicate tests were detected in 57 of the children (0.59%). 10 children have developed diabetes so far, and all had ICA detected beforehand. The likelihood of developing IDD among the ICA-positive children was compared with 2,959 age-matched nondiabetic first degree relatives of IDD probands who were screened for ICA by our laboratory during the same time period and also followed prospectively. Of 103 (3.5%) ICA-positive relatives, 31 have developed IDD. Life table analysis reveals no statistically significant differences in the probability of developing IDD between the ICA-positive schoolchildren and ICA-positive first degree relatives (P = 0.3). The estimated risk of developing IDD by 7 yr in the ICA-positive schoolchildren was 45% (95% confidence interval 15-74%) compared with 43% (confidence interval 22-63%) in the relatives. We conclude that ICA appear to be as predictive of IDD in low-risk schoolchildren as they are in high-risk relatives. These data suggest that it is feasible to predict IDD by screening a general population of schoolchildren for ICA and that those found to be positive could be considered, in addition to relatives, for intervention protocols to prevent the disease.

Sentinel lymph node involvement and a high Breslow index are independent factors of risk for early relapse of melanoma.

AIM: The clinical relevance of sentinel lymph node (SLN) analysis was evaluated prospectively and compared with other known risk factors of relapse in early stage melanoma. METHODS: Surgery was guided by lymphoscintigraphy, blue dye and gamma probe detection. SLN were analysed by haematoxylin eosin (HE) histochemistry and multimarker immunohistochemistry (IHC). Disease free survival (DFS) was evaluated with Kaplan-Meier plots according to different parameters and Cox analyses of variance. RESULTS: From 210 patients a total of 381 SLN were excised. Lymphoscintigraphy identified all excised SLN with only 2 false positive lymphatic lakes. Fifty patients (24%) had tumour positive SLN. With a mean follow-up of 31.3 months, 29 tumour recurrences were observed, 19 (38%) in 50 SLN positive and 10 (6%) in 160 SLN negative patients. Strong predictive factors for early relapse (p < 0.0005) were SLN positivity and a high Breslow index. CONCLUSION: SLN tumour positivity is an independent factor of high risk for early relapse with a higher power of discrimination than the Breslow index.

The association of anti-platelet factor 4/heparin antibodies with early and delayed thromboembolism after cardiac surgery.

Essentials We evaluated antibody status, thromboembolism and survival after cardiac surgery. Positive antibody tests are common - over 50% are seropositive at 30 days. Seropositivity did not increase thromboembolism or impair survival after cardiac surgery. Results show heparin induced thrombocytopenia antibody screening after surgery is not warranted. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a prothrombotic response to heparin therapy with platelet-activating, anti-platelet factor 4 (PF4)/heparin antibodies leading to thrombocytopenia associated with thromboembolism. Objective We tested the hypothesis that anti-PF4/heparin antibodies are associated with thromboembolism after cardiac surgery. Methods This multicenter, prospective cohort study collected laboratory and clinical data up to 30 days after surgery and longer-term clinical follow-up data. The primary outcome variable combined new arterial or venous thromboembolic complications (TECs) with all-cause death until 90 days after surgery. Laboratory analyses included platelet counts and anti-PF4/heparin antibody titers (GTI ELISA), with a confirmatory excess heparin step and serotonin release assay. Chi-square testing was used to test the relationship between our outcome and HIT antibody seropositivity. Results Initially, 1021 patients were enrolled between August 2006 and May 2009, and follow-up was completed in December 2014. Seropositivity defined by OD > 0.4 was common, being almost 20% preoperatively, > 30% by discharge, and > 60% by day 30. Death (1.7% within 30 days) or TECs (69 in total) were more likely if the partient was seronegative (OD < 0.4), but positivity defined by OD > 1.0 or including an excess heparin confirmatory step resulted in equal incidence of death or TECs, whether the patient was seronegative or seropositive. Incorporating the serotonin release assay for platelet-activating antibodies did not alter these findings. Conclusions Seropositivity for anti-PF4/heparin antibodies does not increase the risk of death or thromboembolism after cardiac surgery. Screening is not indicated, and seropositivity should only be interpreted in the context of clinical evidence for HIT. TRIAL REGISTRATION: Duke IRB Protocol #00010736.

Effects of health insurance and race on early detection of cancer.

BACKGROUND: The presence and type of health insurance may be an important determinant of cancer stage at diagnosis. To determine whether previously observed racial differences in stage of cancer at diagnosis may be explained partly by differences in insurance coverage, we studied all patients with incident cases of melanoma or colorectal, breast, or prostate cancer in Florida in 1994 for whom the stage at diagnosis and insurance status were known. METHODS: The effects of insurance and race on the odds of a late stage (regional or distant) diagnosis were examined by adjusting for an individual's age, sex, marital status, education, income, and comorbidity. All P values are two-sided. RESULTS: Data from 28 237 patients were analyzed. Persons who were uninsured were more likely diagnosed at a late stage (colorectal cancer odds ratio [OR] = 1.67, P =.004; melanoma OR = 2.59, P =.004; breast cancer OR = 1.43, P =.001; prostate cancer OR = 1.47, P =.02) than were persons with commercial indemnity insurance. Patients insured by Medicaid were more likely diagnosed at a late stage of breast cancer (OR = 1.87, P<.001) and melanoma (OR = 4.69, P<.001). Non-Hispanic African-American patients were more likely diagnosed with late stage breast and prostate cancers than were non-Hispanic whites. Hispanic patients were more likely to be diagnosed with late stage breast cancer but less likely to be diagnosed with late stage prostate cancer. CONCLUSIONS: Persons lacking health insurance and persons insured by Medicaid are more likely diagnosed with late stage cancer at diverse sites, and efforts to improve access to cancer-screening services are warranted for these groups. Racial differences in stage at diagnosis are not explained by insurance coverage or socioeconomic status.

Pediatric Oncology Group Study of in vitro clonal growth patterns of leukemic cells in childhood acute nonlymphocytic leukemia as a predictor of induction response.

Previous studies have shown that clonal growth patterns of leukemic cells from adult patients with acute nonlymphocytic leukemia (ANLL) have prognostic significance for achieving complete remission (CR). In order to determine if a similar correlation between clonal growth patterns and response to chemotherapy exists in childhood ANLL, bone marrow cells from 189 children with newly diagnosed ANLL were cultured in agar. After 7 days of incubation, colonies (greater than 50 cells), large clusters (20 to 50 cells), and small clusters (4 to 20 cells) were counted. Cultures were analyzed for frequency of clusters and colonies as well as for size of clusters. Two growth patterns significantly associated with poor prognosis for achieving CR were large-cluster growth and high cluster incidence (defined as greater than 400 clusters/10(5) bone marrow cells). The CR rate for the former was 53% (versus 79% for non-Group 1 patients; P = 0.03); the CR rate for the latter was 46% (versus 81% for non-Group 2 patients; P = 0.004). These findings indicate that clonal growth characteristics of leukemic cells from childhood ANLL patients are significantly correlated with response to induction chemotherapy and are useful in identifying a subset of patients with poor prognosis.

Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study.

PURPOSE: A randomized study compared the combination of amsacrine (100 mg/m2/d on days 1 to 5) and etoposide (200 mg/m2/d on days 1 to 3) with the same two agents plus azacitidine (250 mg/m2/d on days 4 to 50) for the therapy of induction-resistant or relapse childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: One hundred sixty-seven assessable children with AML who either had failed to respond to primary induction therapy (group 1, n = 41) or had relapsed (group 2, n = 126) were randomized. RESULTS: Overall, there were 56 complete responses (34%; SE 4%). Among primary refractory patients (group 1), the complete response rate was higher with the three-drug regimen (18% vs 53%, P = .03). In the relapsed patients (group 2), there was no difference in complete response rates related to treatment (31% vs 35%, P = .3). There were 17 early deaths. The major toxicities for both regimens were myelosuppression and infection. CONCLUSION: The overall complete response rate of 34% in this patient population is indicative of effective antileukemic activity. For patients with relapsed leukemia, the addition of azacitidine to etoposide and amsacrine did not improve response. The suggested advantage of the three-drug regimen for induction failures warrants further investigation.

Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience.

PURPOSE: To determine the incidence of clinical cardiotoxicity from anthracycline chemotherapy in children with cancer and to identify associated risk factors. PATIENTS AND METHODS: The study population consisted of 6,493 children with cancer who had received anthracycline chemotherapy on Pediatric Oncology Group (POG) protocols from 1974 to 1990. Cardiotoxicity, defined as congestive heart failure not due to other causes, abnormal measurements of cardiac function that prompted discontinuation of therapy, or sudden death from presumed cardiac causes, was determined by a review of protocol records. RESULTS: Cardiotoxicity was confirmed in 106 patients (1.6%): 58 had congestive heart failure, 43 had changes in measures of cardiac function that prompted the discontinuation of therapy, and five died suddenly from presumed cardiac causes. In a multivariate analysis, factors that contributed to the relative risk (RR) of toxicity were a cumulative anthracycline dose > or = 550 mg/m2 of body-surface area (RR = 5.2), maximal dose > or = 50 mg/m2 (RR = 2.8), female sex (RR = 1.9), black race (RR = 1.7), presence of trisomy 21 (RR = 3.4), and exposure to amsacrine (RR = 2.6). Cardiotoxicity within 1 year after the completion of anthracycline treatment (early cardiotoxicity) represented 89.5% of all cases. CONCLUSION: Early clinical cardiotoxicity in children treated with anthracycline is rare. A high maximal dose, or cumulative dose of anthracycline, female sex, black race, presence of trisomy 21, and treatment with amsacrine increase the risk for anthracycline-associated cardiotoxicity.

A comparison of induction and maintenance therapy for acute nonlymphocytic leukemia in childhood: results of a Pediatric Oncology Group study.

Two hundred fifty-six children with previously untreated acute nonlymphocytic leukemia (ANLL) were evaluated on a Pediatric Oncology Group (POG) phase III randomized trial of both induction and continuation chemotherapies. Induction therapy compared vincristine, cytarabine, and dexamethasone (VADx) with daunorubicin, cytarabine, and thioguanine (DAT). The complete remission (CR) rate using DAT was superior (82% v 61%, P = .02). Postremission therapy consisted of either "standard" two-cycle therapy or a more intensive four-cycle regimen given for 2 years. Overall, there was no difference in outcome for patients randomized to either continuation regimen. The overall complete continuous remission rate (CCR) for the "best" induction/continuation therapy combination at 2 years was .50 (SE = .06), at 3 years was .35 (.04), and at 4 years was .34 (.05). Analysis of selected clinical and laboratory parameters demonstrated differences in induction responses favoring DAT induction but did not impact eventual disease-free survival. There were two subgroups of patients who responded better to four-cycle continuation therapy. These were patients with French-American-British (FAB) M1/M2 (2-year CCR was .20 v .44, P = .01) and patients older than 10 years at diagnosis (.32 v .62, P = .004).

High-dose cytarabine for intensification of early therapy of childhood acute myeloid leukemia: a Pediatric Oncology Group study.

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.