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The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, 3-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low-furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed "Hudson" grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107-140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80% to 125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. Although most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice.

Bland-Altman method comparison studies are common in the medical sciences and are used to compare a new measure to a gold-standard (often costlier or more invasive) measure. The distribution of these differences is summarized by two statistics, the 'bias' and standard deviation, and these measures are combined to provide estimates of the limits of agreement (LoA). When these LoA are within the bounds of clinically insignificant differences, the new non-invasive measure is preferred. Very often, multiple Bland-Altman studies have been conducted comparing the same two measures, and random-effects meta-analysis provides a means to pool these estimates. We provide a framework for the meta-analysis of Bland-Altman studies, including methods for estimating the LoA and measures of uncertainty (i.e., confidence intervals). Importantly, these LoA are likely to be wider than those typically reported in Bland-Altman meta-analyses. Frequently, Bland-Altman studies report results based on repeated measures designs but do not properly adjust for this design in the analysis. Meta-analyses of Bland-Altman studies frequently exclude these studies for this reason. We provide a meta-analytic approach that allows inclusion of estimates from these studies. This includes adjustments to the estimate of the standard deviation and a method for pooling the estimates based upon robust variance estimation. An example is included based on a previously published meta-analysis. Copyright © 2017 John WileySons, Ltd.

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Children's Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

To determine whether the methacholine challenge method used for albuterol can be applied to assess long-acting β2-adrenergic agonist (LABA) bioequivalence, which would require a sufficiently steep dose-response curve.Prospective, unblinded, randomized, 2-way crossover study.University medical center clinical research laboratory.Ten adults, aged 21-58 years, with mild asthma (forced expiratory volume in 1 sec [FEV(1)] ≥ 70% predicted) and a baseline provocational concentration of methacholine required to decrease FEV(1) by 20% (PC(20)) of 4 mg/ml or less completed the study.Patients were randomized to receive a single dose of either 12 or 24 μg of formoterol delivered by a dry powder inhaler; 3-7 days later, at the same time of day, they received the other dose.The FEV(1) was measured before and 1 hour after dosing, followed by performance of a methacholine challenge. Statistical analysis was performed by the 2-sample regression method for crossover studies. The dose-response curve for bronchodilatation was flat; the mean ± SD increase in FEV(1) after formoterol 12 and 24 μg was 14 ± 5% and 14 ± 8%, respectively (p0.05). In contrast, the geometric mean PC20 (95% confidence interval) was 7 mg/ml (2-22 mg/ml) after the 12-μg dose and 16 mg/ml (5-45 mg/ml) after the 24-μg dose (p0.001).Bioassay by methacholine challenge will be useful for bioequivalence studies of LABAs. A sample of at least 28 patients will be required for formoterol when methacholine challenge is performed in an optimal manner. The sample size may differ for other LABAs.

The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials.Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome.The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2 ± 3.7% vs. 50.6 ± 2.4%; P = 0.0007) but similar to POG 9406 (63.5 ± 2.4%; P = 0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥ 100,000/microliter. Day 29 marrow MRD positive (≥ 0.01%) vs. negative patients had 5 year CCR rates of 37.1 ± 7.4% vs. 72.6 ± 4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1 ± 4.6% vs.83.6 ± 6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD0.01%, initial WBC ≥ 100,000/µl, male gender, and day 8 blood MRD0.01% were significant prognostic factors.Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients.

Sleep-related breathing disorders are common in individuals with Prader-Willi syndrome (PWS). The US Food and Drug Administration approved the use of growth hormone in PWS in 2000. Many infants with PWS are being started on growth hormone therapy, but no data exist on the respiratory effects of growth hormone treatment in this age group.To perform overnight polysomnographic studies to evaluate the effects of growth hormone on sleep-related breathing in infants with PWS.Pilot study evaluating overnight polysomnography before and 6 weeks after initiation of growth hormone therapy at a dose of 1 mg/m2 per day in 20 infants from 2 to 21 months of age with genetically confirmed PWS. Polysomnography results were analyzed for frequency and severity of obstructive and central apnea and hypopnea events and the overall apnea-hypopnea index.When data were analyzed for the total group, there were no significant changes in sleep-related disorders before and after institution of growth hormone therapy. However, 12 infants had an increase in the frequency of obstructive events associated with either upper respiratory infections or a diagnosis of gastroesophageal reflux at the second sleep study (after institution of growth hormone therapy). Resolution of these conditions was associated with normalization of polysomnography results on follow-up studies.Overall, growth hormone therapy, per se, had no significant effect on sleep related-breathing disorders in infants with PWS. Infants with upper respiratory infections of gastroesophageal reflux may be at risk for developing more obstructive events after beginning growth hormone treatment. We recommend close monitoring of infants with PWS after they begin growth hormone therapy, especially when they have upper respiratory infections.

Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma (ALCL) are rare in young patients. While a high proportion of adults with PTCL have poor risk disease, pediatric PTCL is not well characterized. This study examines the outcome of localized and advanced PTCL in pediatric patients treated in standardized fashion.We identified 20 pediatric patients diagnosed with PTCL whose tumor cells did not express CD30 and/or ALK, as determined by immunohistochemistry, between 1992 and 2000 on one of two treatment protocols for localized NHL (POG 9219) or advanced stage large cell lymphoma (POG 9315). All cases were centrally reviewed.The median age was 12.6 (range 0.7-16.9)-9 male and 11 female. Histological subtypes in the WHO Classification included PTCL, unspecified (12), extra-nodal NK/T-cell lymphoma of nasal type (4), subcutaneous panniculitis-like T cell lymphoma (1) and enteropathy-type T-cell lymphoma (1). Two cases exhibited both T-cell and histiocyte markers and were reclassified as histiocytic sarcoma per the WHO, although T-lineage remains possible. Of 10 patients with localized disease, only two relapsed and 9 survive. Of 10 patients with advanced disease, six relapsed and five (50%) survive.These results suggest that localized PTCL in children and adolescents is frequently cured with modern therapy, but that advanced stage cases may require novel therapy.

Oral phenylephrine is used as a decongestant, yet there has been no previously published systematic review supporting its efficacy and safety.To assess the efficacy and safety of oral phenylephrine as a nonprescription decongestant.MEDLINE, the Cochrane Central Registry of Controlled Trials, EMBASE, International Pharmaceutical Abstracts, and the Federal Register were searched for English and non-English-language studies published through January 2007 that measured the effects of oral phenylephrine on nasal airway resistance (NAR) in patients with nasal congestion. The retrieved studies were supplemented with information from our personal files and by hand searches of the references in any of the studies. Additionally, a Web of Science Search was conducted using the Cited Reference function for all published clinical trials identified. Studies included in the analysis were randomized, placebo-controlled trials; studies of combination products were excluded. Two investigators independently extracted data on NAR, self-reported decongestant effects, and cardiovascular effects (ie, heart rate, blood pressure) from each of the included studies. Meta-analyses were performed for NAR and cardiovascular effects using a random effects model. Subjective decongestant effects were summarized.Based on 8 unpublished studies that included 138 patients, phenylephrine 10 mg did not affect NAR more than placebo; the mean maximal difference in relative change from baseline between phenylephrine and placebo was 10.1% (95% CI -3.8% to 23.9%). Eight unpublished studies on phenylephrine 25 mg showed a significant reduction of maximal NAR compared with placebo of 27.6% (95% CI 17.5% to 37.7%). There was significant heterogeneity among the studies included in this analysis, which was partially attributable to different laboratories and methods used. Patient-reported decongestion was not consistently better for any phenylephrine dose compared with placebo, and NAR was a more sensitive measurement of efficacy. Phenylephrine showed no consistent effect on heart rate or blood pressure for doses of 25 mg or less.There is insufficient evidence that oral phenylephrine is effective for nonprescription use as a decongestant. The Food and Drug Administration should require additional studies to show the safety and efficacy of phenylephrine.

Purpose: This study was designed to evaluate (1) the efficacy of standard or high-dose cisplatin with etoposide and bleomycin and (2) the role of surgical resection in infants and children with malignant germ cell tumors of the sacrococcygeal region (SCT). Methods: Seventy-four of 317 children presenting to Pediatric Oncology Group (POG)/Children's Cancer Group (CCG) institutions from 1990 through 1996 with malignant germ cell tumors had malignant SCT. There were 62 girls and 12 boys with a median age of 21 months (range, 3 days to 37 months) and median serum alpha-fetoprotein of 35,500 ng/mL. Twelve had undergone resection of a benign SCT as a newborn. Forty-four (59%) had evidence of metastatic disease at time of diagnosis. Presentation by type (Altman classification) was I, 0; II, 2; III, 30; and IV, 42. The initial procedure was biopsy in 45 and resection in 29. Patients were assigned randomly to receive 4 cycles of chemotherapy with etoposide (E) and bleomycin (B) and either high-dose cisplatin (200 mg/m 2 per cycle; HDP) or standard dose cisplatin (100 mg/m 2 per cycle; P). After completion of chemotherapy, 42 of 45 initially treated with biopsy underwent resection. Results: Overall 4-year survival rate is 90% (SE = 4%) and 4-year event-free survival (EFS) is 84% (SE = 6%). Event-free survival data for subgroups of interest are as follows:4-yr EFS% (SE)P ValuesMets (44)88 (6).48No Mets (30)80 (8)HDP EB (37)89 (6).21P EB (37)78 (7)Initial Resection (29)90 (7).50Delayed Resection (42)83 (7)Complete Resection (49)90 (5).19 CR/PRPartial Resection (22)77 (10)Biopsy Only (3)33 (27).005 (3 way) Conclusions: (1) The current survival rate of malignant sacrococcygeal tumors is excellent even with metastases. (2) Delayed surgical resection is not associated with an adverse outcome. (3) In this subset the treatment comparison was inconclusive however, followed the trend in the overall study of more than 300 children in which the high-dose cisplatin group had superior EFS ( P J Pediatr Surg 36:12-17. Copyright © 2001 by W.B. Saunders Company.

In the February 1992 report entitled "A Population-Based Study of Neuroblastoma Incidence, Survival, and Mortality in North America" by Bernstein et al (J Clin Oncol 10:323–329, 1992), the parenthetical ratios that immediately follow the incidence figures per million population were incorrect. The ratios should have reflected cumulative incidence figures based on the geographic- and age-specific rates. Consequently, on page 324, in the Results section, paragraph 2, beginning with the third sentence, the text should read as follows: "The annual incidence rate of neuroblastoma was calculated to be 11.32/106 for children under 15 years of age in Quebec (cumulatively, approximately 1/5,889) and 27.47/106 under 5 years of age (approximately 1/7,281). In the GDV, the rates were 10.58/106 for children under 15 years of age (1/6,301) and 28.03/106 for children under 5 years of age (1/7,135) ... the combined incidence data are 27.75/106 for children under 5 years of age (1/7,207) and 10.95/106 for under 15 years of age (1/6,088). Similarly, in the Discussion section, paragraph 1, the text should read: "Combining ... the annual incidence of neuroblastoma ... is 10.95/106 for children aged 0 to 14 years (approximately 1/6,088) and, ... 27.75/106 for children aged 0 to 4 years. This is approximately 1/7,207 children under the age of 5 years."