Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children's Oncology Group.

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin rescue, and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with "standard-risk" acute lymphoblastic leukemia, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. Children on both studies had significant attention problems, but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive MTX exposure as a major contributor to CNS late effects.

The Medich giant platelet syndrome: two new cases.

Hypogranular platelet disorders in human subjects are relatively rare. They include the gray platelet syndrome, αδ storage pool deficiency, the Hermansky-Pudlak syndrome, and the white platelet syndrome. Perhaps the rarest of them all is the Medich giant platelet disorder. No additional cases of this condition have been reported since description of the first case in 2004. This study describes two children with thrombocytopenia and giant, hypogranular platelets found shortly after birth. Electron microscopic study of their platelets revealed sheets of membrane wrapped into tubes resembling scrolls. The scroll-like structures were open at both ends and often filled with glycogen particles. The abnormal structures are identical to those found in the initial case. As a result, the disorder can now be referred to as the Medich giant platelet syndrome.

Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression.

OBJECTIVE: To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression. METHODS: Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data. RESULTS: 1913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively). CONCLUSION: Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.

Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo-controlled studies.

INTRODUCTION: Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. METHODS: The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. RESULTS: The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. CONCLUSIONS: The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia.

Long-term symptomatic remission of schizophrenia with once-daily extended release quetiapine fumarate: post-hoc analysis of data from a randomized withdrawal, placebo-controlled study.

Despite available effective medications, many patients with schizophrenia do not become completely symptom free. We report analyses of data from a randomized, double-blind, placebo-controlled relapse prevention study of extended release quetiapine fumarate (quetiapine XR) using Remission in Schizophrenia Working Group criteria for symptomatic remission. During 16-week open-label stabilization, patients with stable schizophrenia were switched from their current antipsychotic to quetiapine XR (400, 600 or 800 mg/day flexibly dosed). One hundred and ninety-seven patients were randomized to either quetiapine XR or placebo (planned for 1 year or until relapse). The study was terminated early because the planned interim analysis showed quetiapine XR to be statistically superior to placebo in the primary outcome variable (time to schizophrenia relapse). One hundred and eighty of 195 (92.3%) patients with an available Positive and Negative Syndrome Scale assessment met symptomatic remission criteria at randomization (following 16 weeks' quetiapine XR). The risk of losing symptomatic remission was statistically significantly higher with placebo versus quetiapine XR: hazard ratio 0.39 (95% confidence interval: 0.19-0.81, P=0.009), that is, 61% risk reduction for quetiapine XR-treated versus placebo-treated patients. At 6 months postrandomization, the probability that patients would be in remission was 76% for quetiapine XR and 52% for placebo. Once-daily quetiapine XR was effective in preserving symptomatic remission in the longer-term treatment of patients with schizophrenia.

A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. METHOD: 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. RESULTS: Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. CONCLUSIONS: Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119652.

A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I).

OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder. METHOD: 802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine 600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from August 2005 to May 2007. RESULTS: Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo). Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-treated (both doses), but not lithium-treated, patients showed significant improvements (P < .05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity of Illness and -Change, and Hamilton Anxiety Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium. CONCLUSIONS: Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly differ from placebo on the main measures of efficacy. Both treatments were generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00206141.

A failed 6-week,randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned.

OBJECTIVE: To demonstrate the efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in adults with acute exacerbation of schizophrenia. METHODS: A 6-week, double-blind, randomized, placebo-controlled study. In- or out-patients with a DSM-IV diagnosis of schizophrenia were randomized to fixed-dose quetiapine XR 400, 600, or 800 mg/day, quetiapine immediate release (IR) 800 mg/day, or placebo. Primary endpoint was change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Other efficacy assessments included Clinical Global Impressions (CGI) of Severity (CGI-S) and of Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. RESULTS: 565 patients were randomized; 333 (58.9%) completed the study. Greater numeric improvements in PANSS total score were seen for quetiapine XR (all doses) and quetiapine IR versus placebo at Week 6; the differences were not statistically significant. Secondary efficacy endpoint results were similar. There was not a high placebo response in this study, but rather an attenuation of drug effect. In general, quetiapine XR was well tolerated over 6-weeks' treatment; there were no unexpected AEs. CONCLUSION: The efficacy of quetiapine XR (400, 600, and 800 mg/day) was not established at Week 6. Quetiapine IR, an agent with established efficacy in schizophrenia, also did not separate from placebo at endpoint. Therefore, this is considered a failed study and possible reasons for this are discussed. Quetiapine XR was generally well tolerated and its safety profile was consistent with the known profile of quetiapine.

A 24-week, multicenter, open-label, randomized study to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with olanzapine, quetiapine, or risperidone.

OBJECTIVE: This randomized, 24-week, flexible-dose study compared changes in glucose metabolism in patients with DSM-IV schizophrenia receiving initial exposure to olanzapine, quetiapine, or risperidone. METHOD: The hypothesized primary endpoint was change (baseline to week 24) in area under the curve (AUC) 0- to 2-hour plasma glucose values during an oral glucose tolerance test (OGTT); primary analysis: olanzapine versus quetiapine. Secondary endpoints included mean change in AUC 0- to 2-hour plasma insulin values, insulin sensitivity index, and fasting lipids. The first patient enrolled on April 29, 2004, and the last patient completed the study on October 24, 2005. RESULTS: Mean weight change (kg) over 24 weeks was +3.7 (quetiapine), +4.6 (olanzapine), and +3.6 (risperidone). Based on data from 395 patients (quetiapine, N = 115 [mean dose = 607.0 mg/day], olanzapine, N = 146 [mean dose = 15.2 mg/day], and risperidone, N = 134 [mean dose = 5.2 mg/day]), mean change in AUC 0- to 2-hour glucose value (mg/dL x h) at week 24 was significantly lower for quetiapine versus olanzapine (t = 1.98, df = 377, p = .048). Increases in AUC 0- to 2-hour glucose values were statistically significant with olanzapine (+21.9 mg/dL x h, 95% CI = 11.5 to 32.4 mg/dL x h) and risperidone (+18.8 mg/dL x h, 95% CI = 8.1 to 29.4 mg/dL x h), but not quetiapine (+9.1 mg/dL x h, 95% CI = -2.3 to 20.5 mg/dL x h). AUC 0- to 2-hour insulin values increased statistically significantly with olanzapine (+24.5%, 95% CI = 11.5% to 39.0%), but not with quetiapine or risperidone. Reductions in insulin sensitivity index were statistically significant with olanzapine (-19.1%, 95% CI = -27.9% to -9.3%) and risperidone (-15.8%, 95% CI = -25.1% to -5.4%), but not quetiapine. Total cholesterol and low-density lipoprotein levels increased statistically significantly with olanzapine (+21.1 mg/dL, 95% CI = 13.0 to 29.2 mg/dL, and +20.5 mg/dL, 95% CI = 13.8 to 27.1 mg/dL, respectively) and quetiapine (+13.1 mg/dL, 95% CI = 4.3 to 21.9 mg/dL, and +13.3 mg/dL, 95% CI = 6.1 to 20.5 mg/dL, respectively), but not risperidone. Statistically significant increases in triglycerides (+30.9 mg/dL, 95% CI = 10.9 to 51.0 mg/dL), total cholesterol/high-density lipoprotein (HDL) ratio (0.5, 95% CI = 0.2 to 0.8), and triglyceride/HDL ratio (0.3, 95% CI = 0.0 to 0.6) were observed with olanzapine only. CONCLUSION: The results indicate a significant difference in the change in glucose tolerance during 6 months' treatment with olanzapine versus quetiapine, with significant reductions on olanzapine and risperidone, but not quetiapine; these differential changes were largely explained by changes in insulin sensitivity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00214578.

Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study.

OBJECTIVE: This 6-week, randomized, double-blind study evaluated efficacy and safety of adjunctive extended-release (XR) quetiapine in patients with major depressive disorder (MDD) and an inadequate response to >or= 1 antidepressant. METHOD: Male or female patients aged 18 to 65 years with DSM-IV-TR MDD were randomly assigned to receive quetiapine XR (150 or 300 mg/day) or placebo adjunctive to continuing antidepressant. Primary endpoint was change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Secondary variables included MADRS response (>or= 50% reduction in score from randomization) at weeks 1 and 6, MADRS remission (

Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy treatment for major depressive disorder (MDD). METHOD: This 8-week (6-week active-treatment, randomized phase; 2-week posttreatment drug-discontinuation/tapering phase), multicenter, double-blind, randomized, parallel-group, placebo- and active-controlled, phase 3 study was conducted between April 2006 and May 2007. In total, 612 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined MDD were randomly assigned to quetiapine XR 150 mg/day or 300 mg/day, duloxetine 60 mg/day (active control), or placebo. The primary endpoint was the change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. RESULTS: At week 6, both doses of quetiapine XR (p < .001) and duloxetine (p < .01) significantly reduced mean MADRS total score versus placebo. A significant reduction was seen at week 1 with quetiapine XR 150 mg/day and 300 mg/day versus placebo (p < .01), but not with duloxetine. Response rates (>or= 50% reduction in MADRS total score) at week 6 were significantly higher for both doses of quetiapine XR (p < .01) and duloxetine (p < .05) versus placebo. Remission rates (MADRS score

Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127).

OBJECTIVE: The authors evaluated the efficacy and safety of quetiapine plus lithium or divalproex in the prevention of recurrent mood events in patients with stabilized bipolar I disorder. METHOD: A total of 1,953 patients received open-label quetiapine (400-800 mg/day in flexible, divided doses) with either lithium or divalproex (target serum concentrations 0.5-1.2 meq/liter and 50-125 microg/ml, respectively) for up to 36 weeks. After at least 12 weeks of clinical stability, 628 patients were randomly assigned to double-blind treatment with quetiapine or placebo, in combination with lithium or divalproex, for up to 104 weeks. The primary efficacy measure was time to recurrence of any mood event (mania, depression, or a mixed episode). RESULTS: Fewer patients in the quetiapine group experienced a mood event compared with the placebo group (20.3% versus 52.1%). The hazard ratio for time to recurrence of a mood event was 0.32. Hazard ratios were similar for mania and depression events (0.30 and 0.33, respectively). Sedation, weight increase, and hypothyroidism occurred more frequently in the quetiapine group, as did discontinuations due to adverse events. The incidence and incidence density of a single emergent blood glucose value > or =126 mg/dl were higher in the quetiapine group (12.6% versus 5.4%; 18.44 versus 9.56 patients per 100 patient-years). Adverse events were generally consistent with the known tolerability profile of quetiapine. CONCLUSIONS: In patients stabilized on quetiapine plus lithium or divalproex, continued treatment was associated with a significant risk reduction in the time to recurrence of any mood event compared with placebo and lithium or divalproex.

Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release.

This 10-day, single-center, open-label, randomized, crossover study compared pharmacokinetic profiles and tolerability of extended release quetiapine fumarate (quetiapine XR) with quetiapine immediate release (quetiapine IR) in patients with schizophrenia, schizoaffective disorder or bipolar disorder. After a 2-day lead-in period during which patients received quetiapine XR 300 mg once daily, patients were randomized to quetiapine IR 150 mg twice daily followed by quetiapine XR 300 mg once daily, or quetiapine XR 300 mg once daily followed by quetiapine IR 150 mg twice daily. Pharmacokinetic parameters were evaluated at the end of each 4-day treatment period at steady state. Vital signs, laboratory values, and adverse events (AEs) were recorded throughout the study. The least squares means (90% confidence interval) of the ratio of the area under the plasma concentration-time curve over a 24 h dosing interval (AUC ([0-24 h])) for quetiapine XR/IR was 1.04 (0.92-1.19) and within the pre-defined range set for equivalence (0.80-1.25). Maximum plasma concentration at steady state (C(max)) was approximately 13% lower for quetiapine XR than for quetiapine IR (495.3 versus 568.1 ng/mL), time to reach C(max) (t(max)) was 5 h versus 2 h and mean concentration at the end of 24 h dosing interval (C(min)) was 95.3 versus 96.5 ng/mL, respectively. No patients withdrew from the study owing to AEs and there were no serious AEs or deaths related to study medication. No unexpected AEs, changes in vital signs or laboratory values were observed. These findings suggest that modifying the formulation does not change the overall absorption or elimination of quetiapine, and support emerging clinical evidence for the use of quetiapine XR as a once daily treatment in patients initiating therapy or those established on quetiapine IR.

The psychometric validation of the Sheehan Disability Scale (SDS) in patients with bipolar disorder.

Bipolar disorder (BD) adversely affects daily activities/functioning. The Sheehan Disability Scale (SDS) assesses disability in work/school activities, family relationships, and social functioning, and it evaluates the functional impact of psychiatric disorders. BD outpatients from 21 U.S. sites completed a battery of validated instruments (including the SDS) three times over 8-12 weeks. Instrument reliability (internal consistency, test-retest), validity (construct, convergent validity, known groups) and responsiveness were measured. There were missing data for the SDS in 2% of the 225 subjects with BD. One factor explained 82% of the variance. All SDS items had rotated factor loadings on the first factor >0.90, confirming the appropriateness of the SDS total score. Item-scale correlations surpassed 0.40. There was excellent internal consistency reliability for the SDS total score (Cronbach's alpha=0.89). Test-retest reliability was acceptable for the SDS total score (intraclass correlation coefficient=0.73). Correlations with other instruments demonstrate convergent and divergent validity. The SDS total and item scores significantly discriminated between (self-rated) overall health status, clinician-rated functional status, and clinician-rated depression, evidencing known group validity. The SDS demonstrated ability to detect change over time. The SDS is a valid, reliable measure of disability and is responsive to change over time when used in subjects with BD.

The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia. METHODS: In this 6-week, randomized, double-blind study (5077IL/0041) patients were randomized to receive quetiapine XR (300, 600, or 800 mg/day), quetiapine fumarate immediate release (quetiapine IR) [300 or 600 mg/day], or placebo. Primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Day 42. Secondary variables included PANSS response rate at Day 42 (>/=30% decrease in PANSS total score from baseline) and Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. RESULTS: Of 532 patients randomized, 222 (41.7%) completed the study. Improvements in PANSS total scores from baseline to Day 42 across treatment groups were: quetiapine XR 300 mg/day -5.01, 600 mg/day -13.01 and 800 mg/day -11.17, quetiapine IR 300 mg/day -9.42 and 600 mg/day -6.97, and placebo -5.19; the difference in change was statistically significant only for quetiapine XR 600 mg/day (p = 0.033). There were no statistically significant differences between active treatment groups and placebo for PANSS response rates. Several post hoc analyses were conducted to explain the study efficacy outcome but these were inconclusive. Quetiapine XR was generally well tolerated with the majority of AEs being mild or moderate in intensity and no unexpected AEs. CONCLUSIONS: Superior efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600 mg/day. The safety and tolerability profile of quetiapine XR was similar to that of quetiapine IR.

Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126).

BACKGROUND: This study examined the efficacy and safety of quetiapine in combination with lithium or divalproex compared with placebo with lithium or divalproex in the prevention of recurrent mood events in bipolar I patients, most recent episode mania, depression, or mixed. METHODS: Patients received open-label quetiapine (400-800 mg/day; flexible, divided doses) with lithium or divalproex (target serum concentrations 0.5-1.2 mEq/L and 50-125 microg/mL, respectively) for up to 36 weeks to achieve at least 12 weeks of clinical stability. Patients were subsequently randomized to double-blind treatment with quetiapine (400-800 mg/day) plus lithium/divalproex or placebo plus lithium/divalproex for up to 104 weeks. The primary endpoint was time to recurrence of any mood event. RESULTS: Treatment with quetiapine in combination with lithium/divalproex significantly increased the time to recurrence of any mood event compared with placebo plus lithium/divalproex. The proportion of patients having a mood event was markedly lower in the quetiapine than in the placebo group (18.5% versus 49.0%). The hazard ratio for time to recurrence of a mood event was 0.28 (P<0.001), a mania event 0.30 (P<0.001), and a depression event 0.26 (P<0.001) corresponding to risk reductions of 72%, 70%, and 74%, respectively. During the randomization phase, the most common adverse events occurring in > or =5% in the quetiapine group were somnolence, nasopharyngitis, and headache. Insomnia was more common in the placebo group. During the randomization phase, there was an increase in weight of 0.5 kg in the quetiapine group and a reduction of 1.9 kg in the placebo group. The incidence and incidence density of a single emergent fasting blood glucose value> or =126 mg/dL was higher with quetiapine than with placebo (9.3% versus 4.1%; 17.6 versus 9.5 patients per 100 patient-years). LIMITATIONS: This was an enriched sample of patients with bipolar I disorder responding to treatment with quetiapine plus lithium/divalproex. CONCLUSIONS: Maintenance treatment with quetiapine in combination with lithium/divalproex significantly increased time to recurrence of any event (mania, depression, or mixed) irrespective of the polarity of the index episode compared with placebo with lithium/divalproex. Long-term treatment with quetiapine was generally well-tolerated. Quetiapine with lithium/divalproex can provide an effective long-term treatment option for bipolar I disorder to prevent recurrences not only of mania but also depression.

Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia.

This double-blind, double-dummy study (D1444C00146) evaluated the efficacy and safety of switching patients with clinically stable schizophrenia from quetiapine immediate release (IR) to the same dose of once-daily extended release quetiapine fumarate (quetiapine XR). Patients received quetiapine IR 400-800 mg/day twice daily for 4 weeks, and were then randomized (2 : 1) to a once-daily equivalent dose of quetiapine XR or maintained on IR for 6 weeks. The primary variable was the proportion of patients who discontinued treatment owing to lack of efficacy or whose Positive and Negative Syndrome Scale scores increased by at least 20% from randomization to any visit. In total, 497 patients were randomized to quetiapine XR (n=331) or IR (n=166). Noninferiority (6% margin; one-sided test, 2.5% significance level) was narrowly missed for the primary efficacy variable for the modified intention-to-treat population (9.1%, quetiapine XR; 7.2%, quetiapine IR; difference 1.86%; 95% confidence interval: -3.78, 6.57; P=0.0431), but was shown for the per-protocol population (5.3%, quetiapine XR; 6.2%, quetiapine IR; difference: -0.83%; 95% confidence interval: -6.75, 3.71; P=0.0017). Serious adverse event incidence was low for quetiapine XR and IR; there were no unexpected adverse events. In conclusion, efficacy was maintained without compromising safety/tolerability when switching patients with stable schizophrenia from twice-daily quetiapine IR to once-daily quetiapine XR (400-800 mg/day).

Ewing sarcoma of the mandibular condyle: multidisciplinary management optimizes outcome.

BACKGROUND: Ewing sarcoma (ES) is a rare, primary malignancy of bone that occurs in childhood and early adolescence. Improved methods of diagnosis and treatment have dramatically increased survival over the last 20 years. Treatment mainstays are chemotherapy and surgical tumor resection. ES usually occurs in long bones of the axial skeleton; however, it may rarely arise in facial structures, particularly the mandible. In these cases, resection presents a challenging postsurgical reconstruction. METHODS AND RESULTS: We present the clinical findings and management of a case of ES that developed in the left mandibular condyle of a 15-year-old female. Chemotherapy and segmental mandibulectomy were used to achieve local control. An innovative temporomandibular joint reconstruction was successfully accomplished using a microvascular fibular free flap and conchal cartilage graft. CONCLUSION: Multidisciplinary management in diagnosis, treatment, and restoration of function produced an optimal result that eliminated disease and preserved aesthetics and quality of life.

Induction of protective immune responses against NXS2 neuroblastoma challenge in mice by immunotherapy with GD2 mimotope vaccine and IL-15 and IL-21 gene delivery.

The GD2 ganglioside expressed on neuroectodermal tumor cells is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. Using a syngeneic mouse challenge model with GD2-expressing NXS2 neuroblastoma, we investigated novel strategies for augmenting the effector function of GD2-specific antibody responses induced by a mimotope vaccine. We demonstrated that immunization of A/J mice with DNA vaccine expressing the 47-LDA mimotope of GD2 in combination with IL-15 and IL-21 genes enhanced the induction of GD2 cross-reactive IgG2 antibody responses that exhibited cytolytic activity against NXS2 cells. The combined immunization regimen delivered 1 day after tumor challenge inhibited subcutaneous (s.c.) growth of NXS2 neuroblastoma in A/J mice. The vaccine efficacy was reduced after depletion of NK cells as well as CD4(+) and CD8(+) T lymphocytes suggesting involvement of innate and adaptive immune responses in mediating the antitumor activity in vivo. CD8(+) T cells isolated from the immunized and cured mice were cytotoxic against syngeneic neuroblastoma cells but not against allogeneic EL4 lymphoma, and exhibited antitumor activity after adoptive transfer in NXS2-challenged mice. We also demonstrated that coimmunization of NXS2-challenged mice with the IL-15 and IL-21 gene combination resulted in enhanced CD8(+) T cell function that was partially independent of CD4(+) T cell help in inhibiting tumor growth. This study is the first demonstration that the mimotope vaccine of a weakly immunogenic carbohydrate antigen in combination with plasmid-derived IL-15 and IL-21 cytokines induces both innate and adaptive arms of the immune system leading to the generation of effective protection against neuroblastoma challenge.