Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

A novel sample size formula for the weighted log-rank test under the proportional hazards cure model.

The treatment of cancer has progressed dramatically in recent decades, such that it is no longer uncommon to see a cure or log-term survival in a significant proportion of patients with various types of cancer. To adequately account for the cure fraction when designing clinical trials, the cure models should be used. In this article, a sample size formula for the weighted log-rank test is derived under the fixed alternative hypothesis for the proportional hazards cure models. Simulation showed that the proposed sample size formula provides an accurate estimation of sample size for designing clinical trials under the proportional hazards cure models.

Survival trial design and monitoring using historical controls.

In this paper, we propose a multistage group sequential procedure to design survival trials using historical controls. The formula for the number of events required for historical control trial designs is derived. Furthermore, a transformed information time is proposed for trial monitoring. An example is given to illustrate the application of the proposed methods to survival trial designs using historical controls. Copyright © 2016 John Wiley & Sons, Ltd.

Group Sequential Design for Randomized Phase III Trials under the Weibull Model.

In this article, a parametric sequential test is proposed under the Weibull model. The proposed test is asymptotically normal with an independent increment structure. The sample size for a fixed sample test is derived for the purpose of group sequential trial design. In addition, a multi-stage group sequential procedure is given under the Weibull model by applying the Brownian motion property of the test statistic and sequential conditional probability ratio test methodology.

Prognostic factors that increase the risk for reduced white matter volumes and deficits in attention and learning for survivors of childhood cancers.

OBJECTIVE: In children, CNS-directed cancer therapy is thought to result in decreased cerebral white matter volumes (WMV) and subsequent neurocognitive deficits. This study was designed as a prospective validation of the purported reduction in WMV, associated influential factors, and its relationship to neurocognitive deficits in a very large cohort of both acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) survivors in comparison to an age similar cohort of healthy sibling controls. PROCEDURES: The effects of host characteristics and CNS treatment intensity on WMV were investigated in 383 childhood cancer survivors (199 ALL, 184 BT) at least 12 months post-completion of therapy and 67 healthy siblings that served as a control group. t-Tests and multiple variable linear models were used to assess cross-sectional WMV and its relation with neurocognitive function. RESULTS: BT survivors had lower WMV than ALL survivors, who had less than the control group. Increased CNS treatment intensity, younger age at treatment, and greater time since treatment were significantly associated with lower WMV. Additionally, cancer survivors did not perform as well as the control group on neurocognitive measures of intelligence, attention, and academic achievement. Reduced WMV had a larger impact on estimated IQ among females and children treated at a younger age. CONCLUSIONS: Survivors of childhood cancer that have undergone higher intensity therapy at a younger age have significantly less WMV than their peers and this difference increases with time since therapy. Decreased WMV is associated with significantly lower scores in intelligence, attention, and academic performance in survivors.

Investigating the relationship between COMT polymorphisms and working memory performance among childhood brain tumor survivors.

BACKGROUND: Survivors of childhood brain tumors are at increased risk for neurocognitive impairments, including deficits in abilities supported by frontal brain regions. Catechol-O-methyltransferase (COMT) metabolizes dopamine in the prefrontal cortex, with the Met allele resulting in greater dopamine availability and better performance on frontally mediated tasks compared to the Val allele. Given the importance of identifying resiliency factors against the emergence of cognitive late effects, the current study examined the relationship between COMT genotype and working memory performance among childhood brain tumor survivors. PROCEDURE: Children treated for a brain tumor with conformal radiation therapy (N = 50; mean age at irradiation = 7.41 ± 3.41; mean age at assessment = 13.18 ± 2.88) were administered two computerized measures of working memory (self-ordered search verbal and object tasks). Buccal (cheek) swabs were used to provide tissue from which DNA was extracted. RESULTS: Findings revealed an association between COMT genotype and performance on the self-ordered verbal (P = 0.03) but not object task (P = 0.33). Better performance was found for the Met/Val group compared to either Met/Met or Val/Val. CONCLUSIONS: COMT may indicate a potential resiliency factor against neurocognitive effects of cancer and its treatment; however, there is a need for replication with larger samples of childhood brain tumor survivors.

Slower processing speed after treatment for pediatric brain tumor and acute lymphoblastic leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) and brain tumor (BT) survivors are at risk for post-treatment IQ declines. The extent to which lower scores represent global cognitive decline versus domain-specific impairment remains unclear. This study examined discrepancies between processing speed and estimated IQ (EIQ) scores and identified clinical characteristics associated with score discrepancies in a sample of pediatric cancer survivors. PROCEDURE: Survivors (50 ALL, 50 BT) ages 12-17 years completed cognitive testing. The Wechsler Abbreviated Scale of Intelligence provided an untimed measure of general reasoning ability (EIQ). The age-appropriate Wechsler Intelligence Scale provided a Processing Speed Index (PSI) score. Scores were examined and compared. RESULTS: Survivors' PSI scores were lower than their EIQ scores (BT t(45) =6.3, p<0.001; ALL t(49) =6.9, p<0.001). For BT survivors, lower PSI scores were associated with history of craniospinal irradiation, t(44) =3.3, p<0.01. For ALL survivors, lower PSI scores were associated with male gender, grade retention, and time since diagnosis, F(3, 46) =10.1, p<0.001. Clinically significant EIQ-PSI score discrepancies were identified in 41.3% of BT and 14.0% of ALL survivors. CONCLUSIONS: Many pediatric BT and ALL survivors exhibit slower processing speed than expected for age, whereas general reasoning ability remains largely intact. Risk factors associated with larger EIQ-PSI discrepancies include the following: BT diagnosis, craniospinal irradiation (BT only), male gender, and younger age at diagnosis (ALL only). Grade retention was frequent and associated with lower EIQ scores (both groups) and PSI scores (ALL only). Describing post-treatment cognitive declines using global measures of intellectual ability may underestimate dysfunction or fail to isolate specific underlying deficits contributing to impairment.

Are the psychological needs of adolescent survivors of pediatric cancer adequately identified and treated?

OBJECTIVES: To describe the psychological needs of adolescent survivors of acute lymphoblastic leukemia (ALL) or brain tumor (BT), we examined the following: (i) the occurrence of cognitive, behavioral, and emotional concerns identified during a comprehensive psychological evaluation and (ii) the frequency of referrals for psychological follow-up services to address identified concerns. METHODS: Psychological concerns were identified on measures according to predetermined criteria for 100 adolescent survivors. Referrals for psychological follow-up services were made for concerns previously unidentified in formal assessment or not adequately addressed by current services. RESULTS: Most survivors (82%) exhibited at least one concern across domains: behavioral (76%), cognitive (47%), and emotional (19%). Behavioral concerns emerged most often on scales associated with executive dysfunction, inattention, learning, and peer difficulties. Cranial radiation therapy was associated with cognitive concerns, χ(2) (1, N = 100) = 5.63, p < 0.05. Lower income was associated with more cognitive concerns for ALL survivors, t(47) = 3.28, p < 0.01, and more behavioral concerns for BT survivors, t(48) = 2.93, p < 0.01. Of the survivors with concerns, 38% were referred for psychological follow-up services. Lower-income ALL survivors received more referrals for follow-up, χ(2) (1, N = 41) = 8.05, p < 0.01. Referred survivors had more concerns across domains than non-referred survivors, ALL: t(39) = 2.96, p < 0.01; BT: t(39) = 3.52, p < 0.01. Trends suggest ALL survivors may be at risk for experiencing unaddressed cognitive needs. CONCLUSIONS: Many adolescent survivors of cancer experience psychological difficulties that are not adequately managed by current services, underscoring the need for long-term surveillance. In addition to prescribing regular psychological evaluations, clinicians should closely monitor whether current support services appropriately meet survivors' needs, particularly for lower-income survivors and those treated with cranial radiation therapy.

The utility of parent report in the assessment of working memory among childhood brain tumor survivors.

Childhood brain tumor survivors are at increased risk for neurocognitive impairments, including working memory (WM) problems. WM is typically assessed using performance measures. Little is known about the value of parent ratings for identifying WM difficulties, the relationship between rater and performance measures, or predictors of parent-reported WM problems in this population. Accordingly, the current study examined the utility of parent report in detecting WM difficulties among childhood brain tumor survivors treated with conformal radiation therapy (n = 50) relative to siblings (n = 40) and solid tumor survivors not receiving central nervous system-directed therapy (n = 40). Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Participants were administered WM measures (digit span, self-ordered search tasks). Findings revealed parents rated brain tumor survivors as having significantly more WM problems (p < .01) compared to controls. However, the BRIEF-WM scale demonstrated poor sensitivity and specificity for detecting performance-based problems. Significant, albeit modest, correlations were found between the BRIEF-WM scale and performance measures (r = -.24-.22; p < .05) for the combined group. Age at testing, socioeconomic status, and IQ were significant predictors of parent reported WM problems. Rater and performance measures offer complimentary yet different information in assessing WM, which reiterates the importance of using both within the context of clinical assessment.

Working memory performance among childhood brain tumor survivors.

While longitudinal studies of children treated for brain tumors have consistently revealed declines on measures of intellectual functioning, greater specification of cognitive changes following treatment is imperative for isolating vulnerable neural systems and developing targeted interventions. Accordingly, this cross-sectional study evaluated the performance of childhood brain tumor survivors (n = 50) treated with conformal radiation therapy, solid tumor survivors (n = 40) who had not received central nervous system (CNS) -directed therapy, and healthy sibling controls (n = 40) on measures of working memory [Digit Span and computerized self-ordered search (SOS) tasks]. Findings revealed childhood brain tumor survivors were impaired on both traditional [Digit Span Backward- F(2,127) = 5.98; p < .01] and experimental [SOS-Verbal- F(2,124) = 4.18; p < .05; SOS-Object- F(2,126) = 5.29; p < .01] measures of working memory, and performance on working memory measures correlated with intellectual functioning (Digit Span Backward- r = .45; p < .0001; SOS- r = -.32 to -.26; p < .01). Comparison of performance on working memory tasks to recognition memory tasks (computerized delayed match-to-sample) offered some support for greater working memory impairment. This pattern of findings is consistent with vulnerability in functional networks that include prefrontal brain regions and has implications for the clinical management of children with brain tumors.

The impact of attention on social functioning in survivors of pediatric acute lymphoblastic leukemia and brain tumors.

BACKGROUND: The cognitive late effects experienced by many survivors of pediatric acute lymphoblastic leukemia (ALL) and brain tumors are well-established. The most commonly reported deficit is difficulty with attention. Problems with social functioning have also been identified, but their relationship with cognitive functioning is not well understood. This multi-site, cross-sectional study aimed to examine the impact of attention on social functioning. PROCEDURE: Four hundred sixty nine survivors of ALL and brain tumors (55% ALL; 57% male) completed study procedures, including parent- and teacher-report measures of attention (Conners' Rating Scales, Revised) and parent-report of social functioning [Social Skills Rating System (SSRS)] as part of their screening evaluation for a large clinical trial. Survivors were 12.1 years of age and 4.9 years from the end of treatment at the time of study. RESULTS: Results revealed that survivors' parent-reported attention problems were uniquely associated with their social functioning, relative to known demographic- and treatment-related risk factors. Teacher-reported attention problems, in contrast, were not, despite a significant correlation between the two. Deficits in intelligence and female gender were also significantly associated with poor social functioning. CONCLUSIONS: Attention problems uniquely impact difficulties with social functioning in survivors of pediatric cancer. Future studies will need to further examine the relationship between attention and social functioning in survivors, particularly when assessed by teacher report. Pediatr Blood Cancer 2012; 59: 1290-1295. © 2012 Wiley Periodicals, Inc.

Contrast-enhanced sonography of malignant pediatric abdominal and pelvic solid tumors: preliminary safety and feasibility data.

BACKGROUND: Little information exists regarding pediatric contrast-enhanced US. OBJECTIVE: To assess the safety and feasibility of contrast-enhanced US of pediatric abdominal and pelvic tumors. MATERIALS AND METHODS: This prospective study included eight boys and five girls (mean age, 10.8 years) with abdominal or pelvic tumors. Cohorts of three subjects underwent US with perflutren contrast agent at escalating dose levels. Neurological and funduscopic examination, electrocardiography and continuous pulse oximetry were performed before and after contrast administration. Three radiologists independently scored six imaging parameters on pre- and postcontrast sonography. Inter-reviewer agreement was measured by the Kappa statistic. RESULTS: No neurological, retinal, electrocardiographical or pulse oximetry changes were attributable to the contrast agent. Two subjects reported minor, transient symptoms. Postcontrast US parameter scores improved slightly in 8 of 12 subjects. Postcontrast ultrasound inter-reviewer agreement improved slightly for detection of tumor margins (precontrast = 0.20, postcontrast = 0.26), local tumor invasion (precontrast = -0.01, postcontrast = 0.10) and adenopathy (precontrast = 0.35, postcontrast = 0.44). CONCLUSIONS: Although our sample size is small, perflutren contrast agents appear to be safe and well tolerated in children. Contrast-enhanced sonography of pediatric abdominal and pelvic tumors is feasible, but larger studies are needed to define their safety and efficacy in children.

ADHD and secondary ADHD criteria fail to identify many at-risk survivors of pediatric ALL and brain tumor.

BACKGROUND: Post-treatment attention problems experienced by pediatric cancer survivors have been described as similar to symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD) experienced in physically healthy children. Accordingly, the objectives of this study were to: (a) estimate the rate of occurrence of ADHD and secondary ADHD (SADHD) in a sample of pediatric cancer survivors, (b) compare the rate of ADHD/SADHD among survivors to the prevalence of ADHD in the general population, and (c) examine clinical correlates of ADHD/SADHD in this sample. PROCEDURE: Survivors of pediatric ALL or brain tumor (n = 100) participated in an assessment of attention including a Computerized Performance Measure [Conners' Continuous Performance test-II (CPT-II)], parent and self-report measures (Conners 3), and a structured diagnostic interview for ADHD and other psychological disorders [Diagnostic Interview for Children and Adolescents-IV (DICA-IV)]. RESULTS: Binomial tests revealed that the rate of ADHD/SADHD in our sample (9%) was significantly greater than the lower limits of ADHD prevalence among children in the US (3%; P < 0.001), while no difference was identified compared to the upper limits of ADHD prevalence (7%; P > 0.05). Many additional survivors (>25% of the sample) obtained clinical elevations on Conners 3 scales but did not meet ADHD/SADHD criteria. CONCLUSIONS: Attentional deficits experienced by pediatric cancer survivors do not appear to resemble the clinical presentation of ADHD or SADHD. Many survivors with cognitive and behavioral difficulties related to attention were not identified using this diagnostic approach. Findings offer needed clarification to guide researchers and clinicians in conceptualizing, assessing, and intervening on attentional late effects.

Parent and teacher ratings of attention during a year-long methylphenidate trial in children treated for cancer.

OBJECTIVE: Longitudinally examine attention performance in childhood cancer survivors prescribed methylphenidate (MPH) to ameliorate cognitive late effects, comparing measures for inter-rater and inter-method discrepancies. METHODS: Survivors of acute lymphoblastic leukemia (n = 33) or brain tumor (n = 35), mean age 11.11 ± 0.37 years, completed a 12-month, open-label trial of MPH. Conners' Parent and Teacher Rating Scales were completed at baseline, 1, 3, 6, and 12 months. The Conners' Continuous Performance Test (CPT) was completed at baseline and 12 months. RESULTS: Improved attention was reported after 1 month of MPH (p < .05), with relative stability throughout the trial. Inter-rater agreement was low-to-moderate (ICC = -.06 to .46). Observer ratings correlated with select CPT indices at baseline (p < .05), but not at 12 months. CONCLUSIONS: Childhood cancer survivors' attention improved after 1 month on MPH. Modest agreement between parents and teachers, and low-to-moderate correlations between behavior ratings and performance-based attention measures highlight a need for multimodal assessment.

A flexible multi-stage design for phase II oncology trials.

Phase II trials evaluate whether a new drug or a new therapy is worth further pursuing or certain treatments are feasible or not. A typical phase II is a single arm (open label) trial with a binary clinical endpoint (response to therapy). Although many oncology Phase II clinical trials are designed with a two-stage procedure, multi-stage design for phase II cancer clinical trials are now feasible due to increased capability of data capture. Such design adjusts for multiple analyses and variations in analysis time, and provides greater flexibility such as minimizing the number of patients treated on an ineffective therapy and identifying the minimum number of patients needed to evaluate whether the trial would warrant further development. In most of the NIH sponsored studies, the early stopping rule is determined so that the number of patients treated on an ineffective therapy is minimized. In pharmaceutical trials, it is also of importance to know as early as possible if the trial is highly promising and what is the likelihood the early conclusion can sustain. Although various methods are available to address these issues, practitioners often use disparate methods for addressing different issues and do not realize a single unified method exists. This article shows how to utilize a unified approach via a fully sequential procedure, the sequential conditional probability ratio test, to address the multiple needs of a phase II trial. We show the fully sequential program can be used to derive an optimized efficient multi-stage design for either a low activity or a high activity, to identify the minimum number of patients required to assess whether a new drug warrants further study and to adjust for unplanned interim analyses. In addition, we calculate a probability of discordance that the statistical test will conclude otherwise should the trial continue to the planned end that is usually at the sample size of a fixed sample design. This probability can be used to aid in decision making in a drug development program. All computations are based on exact binomial distribution.

[Clinicopathologic features of calcifying fibrous tumor with reappraisal of its histogenesis].

OBJECTIVE: To study the clinicopathologic features and histogenesis of calcifying fibrous tumor (CFT). METHODS: The clinical manifestations, histopathologic characteristics and immunophenotype were analyzed in 11 cases of CFT. RESULTS: The male-to-female ratio was 5:6, with a mean age of 38 years and age range of 25 to 52 years. The sites of involvement included abdominopelvic cavity (n=6), soft tissue (n=4) and scrotum (n=1). Most patients presented with a gradually enlarging and painless mass. Nearly half of the cases were associated with other diseases or history of inflammation, trauma or surgical intervention. One third of the tumors represented incidental findings and showed no recurrence after resection. Imaging revealed a solitary solid soft tissue mass or multiple nodules with clear borders and associated high-density calcifications. Macroscopically, the tumors were well-circumscribed but non-encapsulated. They ranged from 0.5 to 20.0 cm in diameter and were tan-greyish, round to oval, lobulated or irregular and solid with rubbery consistency. The cut surface was whitish to tan-yellowish, gritty and showed scattered spotty yellowish discoloration corresponding to the foci of dystrophic calcifications. Histologically, CFT was composed of hyalinized fibrous tissue and thickened vessel walls with interspersed bland spindly fibroblastic cells, scattered psammomatous calcifications, dystrophic calcification and lymphoplasmacytic infiltration. In addition, focal cloak-like polymorph infiltration at the tumor periphery and entrapment of adipocytes and nerves were demonstrated in some cases. Foci resembling solitary fibrous tumor, fibromatosis, keloid or inflammatory myofibroblastic tumor were observed. Immunohistochemical study showed that the tumor cells were diffusely positive for vimentin and focally positive for CD34, factor VIII-related antigen and beta-catenin. The admixed plasma cells were notably IgG positive, with more than 50% being IgG4 positive. CONCLUSIONS: CFT has characteristic histopathologic manifestations and shows morphologic and immunohistochemical overlaps with known IgG4-related sclerosing diseases. It is possible that CFT may represent another example of IgG4-related diseases. It often runs a benign clinical course, with rare recurrence after surgical resection. Previous inflammation and trauma may be the precipitating factors of CFT.

Predicting methylphenidate response in long-term survivors of childhood cancer: a randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To investigate the methylphenidate (MPH) response rate among childhood survivors of acute lymphoblastic leukemia (ALL) and brain tumors (BTs) and to identify predictors of positive MPH response. METHODS: Cancer survivors (N = 106; BT = 51 and ALL = 55) identified as having attention deficits and learning problems participated in a 3-week, double-blind, crossover trial consisting of placebo, low-dose MPH (0.3 mg/kg), and moderate-dose MPH (0.6 mg/kg). Weekly teacher and parent reports on the Conners' Rating Scales were gathered. RESULTS: Following moderate MPH dose, 45.28% of the sample was classified as responders. Findings revealed that more problems endorsed prior to the medication trial on parent and teacher ratings were predictive of positive medication response (p < .05). CONCLUSIONS: MPH significantly reduces attention problems in a subset of childhood cancer survivors. Parent and teacher ratings may assist in identifying children most likely to respond to MPH so prescribing may be optimally targeted.

Prospective study of avian influenza transmission to humans in Egypt.

BACKGROUND: The highly pathogenic avian influenza (HPAI) H5N1 virus remains a public health threat and continues to cause outbreaks among poultry as well as human infections. Since its appearance, the virus has spread to numerous geographic areas and is now considered endemic in Egypt and other countries. Most studies on human H5N1 cases were conducted to investigate outbreak situations and were not designed to address fundamental questions about the epidemiology of human infection with H5N1 viruses. Our objective for this study is to answer these questions by estimating the prevalence and incidence rates of human cases and determine associated risk and protective factors in areas where H5N1 viruses are endemic. METHODS/DESIGN: We designed a 3-year prospective cohort study of 1000 individuals of various exposure levels to poultry in Egypt. At onset, we will collect sera to estimate baseline antibody titers against AI viruses H4-H16. Two follow-up visits are scheduled at 1-year intervals following initial enrollment. At follow-up, we will also collect sera to measure changes in antibody titers over time. Thus, annual prevalence rates as well as incidence rates of infection will be calculated. At each visit, exposure and other data will be collected using a specifically tailored questionnaire. This data will be used to measure risk and protective factors associated with infection. Subjects will be asked to contact the study team any time they have influenza-like illness (ILI). In this case, the study team will verify infection by rapid influenza A test and obtain swabs from the subject's contacts to isolate and characterize viruses causing acute infection. DISCUSSION: Epidemiologic studies at the influenza human-animal interface are rare, hence many questions concerning transmission, severity, and extent of infection at the population level remain unanswered. We believe that our study will help tackle and clarify some of these issues.

Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study.

BACKGROUND: Therapy for ependymoma includes aggressive surgical intervention and radiotherapy administered by use of methods that keep the risk of side-effects to a minimum. We extended this treatment approach to include children under the age of 3 years with the aim of improving tumour control. METHODS: Between July 11, 1997, and Nov 18, 2007, 153 paediatric patients (median age 2.9 years [range 0.9-22.9 months]) with localised ependymoma were treated. 85 patients had anaplastic ependymoma; the tumours of 122 were located in the infratentorial region, and 35 had received previous chemotherapy. Patients received conformal radiotherapy after definitive surgery (125 patients had undergone gross total, 17 near total, and 11 subtotal resection). Doses of 59.4 Gy (n=131) or 54.0 Gy (n=22) were prescribed to a 10 mm margin around the target volume. Disease control, patterns of failure, and complications were recorded for patients followed over 10 years. Overall survival, event-free survival (EFS), cumulative incidence of local recurrences, and cumulative incidence of distant recurrences were assessed. Variables considered included tumour grade, tumour location, ethnic origin, sex, age when undergoing conformal radiotherapy, total radiotherapy dose, number of surgical procedures, surgery extent, and preradiotherapy chemotherapy. FINDINGS: After a median follow-up of 5.3 years (range 0.4-10.4), 23 patients had died and tumour progression noted in 36, including local (n=14), distant (n=15), and combined failure (n=7). 7-year local control, EFS, and overall survival were 87.3% (95% CI 77.5-97.1), 69.1% (56.9-81.3), and 81.0% (71.0-91.0), respectively. The cumulative incidences of local and distant failure were 16.3% (9.6-23.0) and 11.5% (5.9-17.1), respectively. In the 107 patients treated with immediate postoperative conformal radiotherapy (without delay or chemotherapy), 7-year local control, EFS, and overall survival were 88.7% (77.9-99.5), 76.9% (63.4-90.4), and 85.0% (74.2-95.8), respectively; the cumulative incidence of local and distant failure were 12.6% (5.1-20.1), and 8.6% (2.8-14.3), respectively. The incidence of secondary malignant brain tumour at 7 years was 2.3% (0-5.6) and brainstem necrosis 1.6% (0-4.0). Overall survival was affected by tumour grade (anaplastic vs differentiated: HR 3.98 [95% CI 1.51-10.48]; p=0.0052), extent of resection (gross total vs near total or subtotal: 0.16 [0.07-0.37]; p<0.0001), and ethnic origin (non-white vs white: 3.0 [1.21-7.44]; p=0.018). EFS was affected by tumour grade (anaplastic vs differentiated: 2.52 [1.2705.01]; p=0.008), extent of resection (gross total vs near total or subtotal: 0.20 [0.11-0.39]; p<0.0001]), and sex (male vs female: 2.19 [1.03-4.66]; p=0.042). Local failure was affected by extent of resection (gross total vs near total or subtotal: 0.16 [0.067-0.38]; p<0.0001), sex (male vs female: 3.85 [1.10-13.52]; p=0.035), and age (<3 years vs >/=3 years: 3.25 [1.30-8.16]; p=0.012). Distant recurrence was only affected by tumour grade (anaplastic vs differentiated: 4.1 [1.2-14.0]; p=0.017). INTERPRETATION: Treatment of ependymoma should include surgery with the aim of gross-total resection and conformal, high-dose, postoperative irradiation. Future trials might consider treatment stratification based on sex and age.

A pharmacokinetics study of orally administered higenamine in rats using LC-MS/MS for doping control analysis.

According to WADA guidelines, the presence of Higenamine (HG) in urine should not be ≥10 ng/mL. HG is widely found in materials used in Chinese herbal medicines as well as food and additives. This paper is the first method wherein a rat model has been used to evaluate the pharmacokinetics of orally administered HG by LC-MS/MS and would be helpful in doping control analysis. The method was found to be linear over a concentration range of 0.5(lower limit of quantification, LLOQ)-500 ng/mL for plasma and 0.5(LLOQ)-1000 ng/mL for urine. The values for intra- and inter-day accuracy and precision did not deviate by >12.25% for HG in plasma and 5.87% in urine. Extraction recoveries of HG were 70.30-86.71% from plasma and 74.93%-79.29% from urine. HG was stable in plasma and urine after the extraction process and when exposed to different storage conditions. The findings of this study could provide some reference value for the assessment of HG misuse and for the control of intake and external application of HG-related materials (foods and medicinal herbs). Our key findings are that high levels of external application or oral administration of HG-rich materials may lead to a positive urine test for HG in athletes.