11C-CHO PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas.

OBJECTIVE: We explored the clinical values of (11)C-choline ((11)C-CHO) PET in optimization of target volume delineation and treatment regimens in postoperative radiotherapy for brain gliomas. METHODS: Sixteen patients with the pathological confirmation of the diagnosis of gliomas prior to receiving radiotherapy (postoperative) were included, and on whom both MRI and CHO PET scans were performed at the same position for comparison of residual tumors with the two techniques. (11)C-CHO was used as the tracer in the PET scan. A plain T1-weighted, T2-weighted and contrast-enhanced T1-weighted imaging scans were performed in the MRI scan sequence. The gliomas' residual tumor volume was defined as the area with CHO-PET high-affinity uptake and metabolism (V(CHO)) and one with MRI T1-weighted imaging high signal intensity (V(Gd)), and was determined by a group of experienced professionals and clinicians. RESULTS: (1) In CHO-PET images, the tumor target volume, i.e., the highly metabolic area with a high concentration of isotopes (SUV 1.016-4.21) and the corresponding contralateral normal brain tissues (SUV0.1-0.62), was well contrasted, and the boundary between lesions and surrounding normal brain tissues was better defined compared with MRI and (18)F-FDG PET images. (2) For patients with brain gliomas of WHO Grade II, the SUV was 1.016-2.5; for those with WHO Grades III and IV, SUVs were >26-4.2. (3) Both CHO PET and MRI were positive for 10 patients and negative for 2 patients. The residual tumor consistency between these two studies was 75%. Four of the 10 CHO-PET-positive patients were negative on MRI scans. The maximum distance between V(Gd) and V(CHO) margins was 1.8 cm. (4) The gross tumor volumes (GTVs) and the ensuing treatment regimens were changed for 31.3% (5/16) of patients based on the CHO-PET high-affinity uptake and metabolism, in which the change rate was 80% (4/5), 14.3 % (1/7) and 0% (0/4) for patients with WHO Grade II III, and IV gliomas, respectively. CONCLUSION: Our data demonstrate that difference exists between CHO PET and MRI by which to judge and identify residual tumor for patients with brain gliomas. CHO PET is considered to be a supplementary diagnostic approach for MRI. Biological tumor target volume (BTV) displayed in the CHO PET images is useful in determining or delineating the radiotherapy target volume and making decisions in selecting treatment regimens. Tumor target volume may be defined more accurately and rationally when the CHO PET is combined with MRI.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Early childhood stimulation benefits adult competence and reduces violent behavior.

OBJECTIVE: An estimated 178 million children younger than 5 years in developing countries experience linear growth retardation and are unlikely to attain their developmental potential. We aimed to evaluate adult benefits from early childhood stimulation and/or nutritional supplementation in growth-retarded children. METHODS: In Kingston, Jamaica, 129 growth-retarded children aged 9 to 24 months took part in a 2-year trial of nutritional supplementation (1 kg milk-based formula per week) and/or psychosocial stimulation (weekly play sessions to improve mother-child interaction). We assessed IQ, educational attainment, and behavior at 22 years old in 105 participants. We used multivariate regressions, weighted to adjust for loss to follow-up, to determine treatment benefits. RESULTS: We found no significant benefits from supplementation. Participants who received stimulation reported less involvement in fights (odds ratio: 0.36 [95% confidence interval (CI) 0.12-1.06]) and in serious violent behavior (odds ratio: 0.33 [95% CI: 0.11-0.93]) than did participants with no stimulation. They also had higher adult IQ (coefficient: 6.3 [95% CI: 2.2-10.4]), higher educational attainment (achievement, grade level attained, and secondary examinations), better general knowledge, and fewer symptoms of depression and social inhibition. CONCLUSIONS: Early psychosocial intervention had wide-ranging benefits in adulthood that are likely to facilitate functioning in everyday life. The reductions in violent behavior are extremely important given the high levels of violence in many developing countries. The study provides critical evidence that early intervention can lead to gains in adult functioning.

Tumor regrowth between surgery and initiation of adjuvant therapy in patients with newly diagnosed glioblastoma.

To assess incidence and degree of regrowth in glioblastoma between surgery and radiation therapy (RT) and to correlate regrowth with presurgical imaging and survival, we examined images of 32 patients with newly diagnosed glioblastoma who underwent MR spectroscopic imaging (MRSI), perfusion-weighted imaging (PWI), and diffusion-weighted imaging (DWI) prior to surgery, after surgery, and prior to RT/temozolomide. Contrast enhancement (CE) in the pre-RT MR image was compared with postsurgical DWI to differentiate tumor growth from postsurgical infarct. MRSI and PWI parameters were analyzed prior to surgery and pre-RT. Postsurgical MRI indicated that 18 patients had gross total and 14 subtotal resections. Twenty-one patients showed reduced diffusion, and 25 patients showed new or increased CE. In eight patients (25%), the new CE was confined to areas of postsurgical reduced diffusion. In the other 17 patients (53%), new CE was found to be indicative of tumor growth or a combination of tumor growth and surgical injury. Higher perfusion and creatine within nonenhancing tumor in the presurgery MR were associated with subsequent tumor growth. High levels of choline and reduced diffusion in pre-RT CE suggested active metabolism and tumor cell proliferation. Median survival was 14.6 months in patients with interim tumor growth and 24 months in patients with no growth. Increased volume or new onset of CE between surgery and RT was attributed to tumor growth in 53% of patients and was associated with shorter survival. This suggests that reducing the time between surgery and adjuvant therapy may be important. The acquisition of metabolic and physiologic imaging data prior to adjuvant therapy may also be valuable in assessing regions of new CE and nonenhancing tumor.

Early childhood stunting is associated with poor psychological functioning in late adolescence and effects are reduced by psychosocial stimulation.

Stunting is associated with deficits in cognition and school achievement from early childhood to late adolescence; however, there has been little investigation of emotional and behavioral outcomes. The objective of this study was to determine whether linear growth retardation (stunting) in early childhood is associated with poorer psychological functioning in late adolescence. The study was a prospective cohort study of stunted and nonstunted children. Participants were identified at age 9-24 mo by a survey of poor neighborhoods in Kingston, Jamaica, and a 2-y intervention trial of supplementation and stimulation was conducted in the stunted children. Psychological functioning was assessed at age 17 y in 103 of 129 stunted children enrolled and 64 of 84 nonstunted participants. Anxiety, depressive symptoms, self-esteem, and antisocial behavior were reported by participants using interviewer-administered questionnaires and attention deficit, hyperactivity, and oppositional behavior were reported by parent interviews. The stunted participants reported significantly more anxiety (regression coefficient = 3.03; 95% CI = 0.99, 5.08) and depressive symptoms (0.37; 95% CI = 0.01, 0.72) and lower self-esteem (-1.67; 95% CI = -0.38, -2.97) than nonstunted participants and were reported by their parents to be more hyperactive (1.29; 95% CI = 0.12, 2.46). Effect sizes were 0.4-0.5 SD. Participants who received stimulation in early childhood differed from the nonstunted group in hyperactivity only. Children stunted before age 2 y thus have poorer emotional and behavioral outcomes in late adolescence. The findings expand the range of disadvantages associated with early stunting, which affects 151 million children <5 y old in developing countries.

Effects of psychosocial stimulation and dietary supplementation in early childhood on psychosocial functioning in late adolescence: follow-up of randomised controlled trial.

OBJECTIVE: To determine whether dietary supplementation or psychosocial stimulation given to growth retarded (stunted) children age 9-24 months has long term benefits for their psychosocial functioning in late adolescence. DESIGN: Sixteen year follow-up study of a randomised controlled trial. SETTING: Poor neighbourhoods in Kingston, Jamaica. PARTICIPANTS: Of 129 stunted children identified at age 9-24 months, 103 adolescents aged 17-18 were followed up. INTERVENTION: Supplementation with 1 kg milk based formula each week or psychosocial stimulation (weekly play sessions with mother and child), or both, for two years. MAIN OUTCOME MEASURES: Anxiety, depression, self esteem, and antisocial behaviour assessed by questionnaires administered by interviewers; attention deficit, hyperactivity, and oppositional behaviour assessed by interviews with parents. RESULTS: Primary analysis indicated that participants who received stimulation had significantly different overall scores from those who did not (F = 2.047, P = 0.049). Supplementation had no significant effect (F = 1.505, P = 0.17). Participants who received stimulation reported less anxiety (mean difference - 2.81, 95% confidence interval - 5.02 to - 0.61), less depression (- 0.43, - 0.78 to - 0.07), and higher self esteem (1.55, 0.08 to 3.02) and parents reported fewer attention problems (- 3.34, - 6.48 to - 0.19). These differences are equivalent to effect sizes of 0.40-0.49 standard deviations. CONCLUSIONS: Stimulation in early childhood has sustained benefits to stunted children's emotional outcomes and attention.

A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma.

PURPOSE: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). METHODS AND MATERIALS: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. RESULTS: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.

Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma.

OBJECT: Convection-enhanced delivery (CED) is a novel method for delivering therapeutic agents to infiltrative brain tumor cells. For agents administered by CED, changes on magnetic resonance (MR) imaging directly resulting from catheter placement, infusion, and the therapeutic compound may confound any interpretation of tumor progression. As part of an ongoing multiinstitutional Phase I study, 14 patients with recurrent malignant glioma underwent CED of interleukin (IL) 13-PE38QQR, a recombinant cytotoxin consisting of human IL-13 conjugated with a truncated Pseudomonas exotoxin. Serial neuroradiographic changes were assessed in this cohort of patients. METHODS: Patients were treated in two groups: Group 1 patients received IL13-PE38QQR before and after tumor resection; Group 2 patients received infusion only after tumor resection. Preoperative and postinfusion MR images were obtained prospectively at specified regular intervals. Changes were noted along catheter tracks on postresection MR images obtained in all patients. A simple grading system was developed to describe these changes. When MR imaging changes appeared to be related to IL1 3-PE38QQR, patients were followed up without instituting new antitumor therapy. CONCLUSIONS: As CED of therapeutic agents becomes more common, clinicians and investigators must become aware of associated neuroimaging changes that should be incorporated into toxicity assessment. We have developed a simple grading system to facilitate communication about these changes among investigators. Biological imaging modalities that could possibly distinguish these changes from recurrent tumor should be evaluated. In this study the authors demonstrate the challenges in determining efficacy when surrogate end points such as time to tumor progression as defined by new or progressive contrast enhancement on MR imaging are used with this treatment modality.

Current chemotherapy for glioblastoma.

INTRODUCTION: Glioblastoma multiforme continues to be associated with a dismal prognosis, despite aggressive therapy. What limited therapeutic impact that has been made has come via multimodality treatment in which chemotherapy plays an important role. In this manuscript, we review current chemotherapy options for glioblastomas. METHODS: The current literature concerning glioblastoma multiforme chemotherapy was reviewed. In addition to a review of landmark references, a MEDLINE search of the literature published from January 2000 to November 2002 was performed using the key words "chemotherapy AND malignant glioma" and limiting responses to clinical trials. RESULTS: Several cytotoxic chemotherapeutic agents that are efficacious in treating glioblastoma are in common clinical use. These can be classified as first-line or second-line agents, depending on their efficacy. In addition, cytostatic chemotherapy agents are beginning to play a role in glioblastoma treatment. Finally, new methods to deliver high chemotherapy doses to brain tumors hold promise for future therapies. CONCLUSIONS: Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact. Strategies currently in clinical trials may improve this impact more in the future.

Nutritional supplementation, psychosocial stimulation, and growth of stunted children: the Jamaican study

The benefits of nutritional supplementation, with or without psychosocial stimulation, on the growth of stunted children were evaluated. Children aged 9-24 mo with lengths < -2 SD of the National Center of Health Statistics references (n = 129) were randomly assigned to four groups: control, nutritional supplementation, stimulation, and both interventions. A fifth group with lengths > -1 SD was also enrolled. Length, weight, head and arm circumferences, and triceps and subscapular skinfold thicknesses were measured on enrollment and 6 and 12 mo later. Multiple-regression analysis was used to determine the effects of the interventions in which age, sex, initial status, initial dietary intake, and several socioeconomic variables were controlled for. Stimulation had no effect on growth and there was no interaction between the interventions. After 12 mo supplemented children had significantly increased length, weight, and head circumference (all P < 0.01). The effects of supplementation were not cumulative but occurred in the first 6 mo.(AU)