Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m, days 1 to 5; M6620 210 mg/m, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

Erythromycin produced an important pharmacokinetic interaction with felodipine by inhibition of drug metabolism. Although erythromycin and grapefruit juice shared a common mechanism, erythromycin likely reduced felodipine biotransformation at the gut wall and liver, whereas single-dose grapefruit juice had an effect mainly at the gut wall.

Objective The purpose of this study was to compare the accuracy of transabdominal sonography and magnetic resonance imaging (MRI) for prenatal diagnosis of placenta accreta. Methods A historical cohort study was undertaken at 3 institutions identifying women at risk for placenta accreta who had undergone both sonography and MRI prenatally. Sonographic and MRI findings were compared with the final diagnosis as determined at delivery and by pathologic examination. Results Thirty-two patients who had both sonography and MRI prenatally to evaluate for placenta accreta were identified. Of these, 15 had confirmation of placenta accreta at delivery. Sonography correctly identified the presence of placenta accreta in 14 of 15 patients (93% sensitivity; 95% confidence interval [CI], 80%–100%) and the absence of placenta accreta in 12 of 17 patients (71% specificity; 95% CI, 49%–93%). Magnetic resonance imaging correctly identified the presence of placenta accreta in 12 of 15 patients (80% sensitivity; 95% CI, 60%–100%) and the absence of placenta accreta in 11 of 17 patients (65% specificity; 95% CI, 42%–88%). In 7 of 32 cases, sonography and MRI had discordant diagnoses: sonography was correct in 5 cases, and MRI was correct in 2. There was no statistical difference in sensitivity (P = .25) or specificity (P = .5) between sonography and MRI. Conclusions Both sonography and MRI have fairly good sensitivity for prenatal diagnosis of placenta accreta; however, specificity does not appear to be as good as reported in other studies. In the case of inconclusive findings with one imaging modality, the other modality may be useful for clarifying the diagnosis.

A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.

Objective. The purpose of this study was to evaluate the association between the second-trimester fetal biparietal diameter/nasal bone length (BPD/NBL) ratio and trisomy 21. Methods. Thirty-one cases of trisomy 21 for which complete ultrasound images included the nasal bone were identified from the University of Washington prenatal diagnosis database and matched to 136 euploid fetuses based on maternal age, indication for referral, and gestational age. Results. The mean NBL was shorter (mean ± SD, 2.3 ± 1.7 mm versus 3.9 ± 1.2 mm; P < .001) and the BPD/NBL ratio was greater (17.7 [range, 6.2-114] versus 11.7 [range, 5.8-80]; P < .001) in the fetuses with trisomy 21. The risk of trisomy 21 increased 2.4-fold (95% confidence interval [CI], 1.7-3.4) with every 1-mm decrease in NBL and increased 1.08-fold (95% CI, 1.03-1.12) with each unit increase in the BPD/NBL ratio (P < .001). A multiple logistic regression model was constructed and included the BPD/NBL ratio, maternal indications (age ≥35 years, positive serum screening results, or both, yielding a risk of <1 per 270 for trisomy 21), and sonographic markers as covariates. The BPD/NBL ratio was found to be an independent predictor of trisomy 21 (odds ratio, 1.08; 95% CI, 1.03-1.11). An analysis of receiver operating characteristic curves revealed an improvement after the BPD/NBL ratio was added to a model containing the current second-trimester screening based on maternal age, serum screening, and sonographic markers (receiver operating characteristic curve area, mean ± SE, 0.89 ± 0.03 for the model with the BPD/NBL ratio versus 0.76 ± 0.06 without the BPD/NBL ratio; P = .009). Conclusions. The secondtrimester BPD/NBL ratio was a significant and independent predictor of trisomy 21. An assessment of the BPD/NBL ratio may improve the diagnosis of trisomy 21 when used with current prenatal screening practices. Key words: nasal bone length; screening; trisomy 21; ultrasound. Current second-trimester screening for aneuploidy includes maternal serum screening and targeted ultrasound evaluation. A number of sonographic abnormalities or "soft markers" have been associated with trisomy 21; some authors have combined these results to provide a risk score or probability for trisomy 21. 3,4 The goal of such prenatal screening programs is accurate detection of fetal aneuploidy and avoidance of unnecessary invasive diagnostic testing. For this purpose, ultrasound has proved to be an invaluable diagnostic and screening tool. The absence of the fetal nasal bone on prenatal sonogra- Received December 6, 2004, from the Department of Obstetrics and Gynecology, Division of MaternalFetal Medicine of Perinatal Medicine (L.T.T., D.B.C., S.B.U., L.E.S.), and Department of

Background:There remains an unmet medical need for new treatments for patients with sickle cell disease (SCD). Increased oxidant stress plays a major part in the pathophysiology of sickle cell disease. It can lead to disturbance of cell membranes, exposure of adhesion molecules and damage to the contents of the sickle red blood cells (sRBC). Previous work from our laboratory has demonstrated enhancement of nicotinamide adenine dinucleotide (NAD) in sRBC by supplementation with a precursor of NAD, L-glutamine. A multi-center Phase 2 placebo-controlled trial in patients with SCD utilizing oral prescription grade L-glutamine resulted in a trend for a decrease in the incidence of painful crises at 24 weeks and a statistically significant decrease in hospitalization during the same time period in the L-glutamine group without increased adverse events. Based on these results, a large multicenter Phase 3 clinical trial was undertaken to evaluate the efficacy and safety of prescription grade L-glutamine therapy in patients with SCD. Methods: A randomized (2:1), double-blind, placebo-controlled, parallel-group trial was conducted at 31 sites across the United States. Subjects were stratified by hydroxyurea usage. Eligibility criteria included patients ≥ 5 years of age with documented diagnoses of HbSS or HbS/β0-thalassemia with at least two documented episodes of sickle cell crises (SCC) diagnosed in a medical facility during the 12 months prior to screening. Pregnant women and patients with uncontrolled liver disease or renal insufficiency were excluded. Prescription grade L-glutamine at 0.6 g/kg/day (max 30 g), or placebo, was taken in two divided doses. Daily dose was rounded to the closest 10 g. The study drug was given for 48 weeks, then was tapered to zero over 3 weeks and a final evaluation visit was made 2 weeks after last dose. The primary endpoint was number of SCC; secondary endpoints include rates of hospitalization and adverse events; additional analyses include cumulative hospital days, incidence of acute chest syndrome (ACS) and time to first crises. Results:A total of 230 patients were enrolled; ages 5-58; 53.9 % female. 152 were assigned to L-glutamine and 78 to placebo; the groups were well balanced for clinical characteristics. The median incidence of SCC was significantly lower in the treatment group compared to the placebo group (3 events vs. 4 respectively; p=0.008); The median incidence of hospitalization was significantly lower in the treatment group compared to placebo group (2 events vs. 3 events respectively; p=0.005); Median cumulative hospital days were significantly lower by 41% in the treatment group (6.5 days) compared to the placebo group (11 days) (p=0.022); 11.9 % of the L-glutamine group and 26.9% of the placebo group were affected by acute chest syndrome (ACS) (p=0.006). The median time to first crisis was 54 days in placebo group and 87 days in treatment group (p=0.010). Adverse events in the treatment arm were similar to those observed in the placebo arm. Statistically significant improvements for the frequency of painful crises and hospitalization persisted with analysis stratified by hydroxurea use, age, and gender. Conclusion: This Phase 3 study in SCD demonstrated that treatment with prescription grade L-glutamine provided clinical benefit over placebo by reducing the frequency of painful crises and hospitalization. Additional clinical benefit was observed when evaluating ACS, time to first crises and duration of hospital stay. There was no increase in adverse events compared to placebo. Prescription oral L-glutamine is easy to administer and does not require special monitoring. Disclosures Niihara: Emmaus Medical Inc: Employment, Equity Ownership. Tran:Emmaus Medical Inc: Employment, Equity Ownership. Razon:Emmaus Medical Inc: Employment. Macan:Emmaus Medical Inc: Employment. Stark:Emmaus Medical Inc: Employment, Equity Ownership. Wun:Emmaus Medical Inc: Consultancy; Pfizer: Steering Committee Other. Adams-Graves:Emmaus Medical Inc: Consultancy.

Intrathecal topotecan appeared to be effective and safe in adult patients with NM.