Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.     

Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

BACKGROUND: Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. METHODS: Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS: Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. CONCLUSIONS: The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.     

Understanding the minimum clinically important difference: a review of concepts and methods.

BACKGROUND CONTEXT: The effectiveness of spinal surgery as a treatment option is currently evaluated through the assessment of patient-reported outcomes (PROs). The minimum clinically important difference (MCID) represents the smallest improvement considered worthwhile by a patient. The concept of an MCID is offered as the new standard for determining effectiveness of a given treatment and describing patient satisfaction in reference to that treatment. PURPOSE: Our goal is to review the various definitions of MCID and the methods available to determine MCID. STUDY DESIGN: The primary means of determining the MCID for a specific treatment are divided into anchor-based and distribution-based methods. Each method is further subdivided and examined in detail. METHODS: The overall limitations of the MCID concept are first identified. The basic assumptions, statistical biases, and shortcomings of each method are examined in detail. RESULTS: Each method of determining the MCID has specific shortcomings. Three general limitations in the accurate determination of an MCID have been identified: the multiplicity of MCID determinations, the loss of the patient's perspective, and the relationship between pretreatment baseline and posttreatment change scores. CONCLUSIONS: An ideal means of determining the MCID for a given intervention is yet to be determined. It is possible to develop a useful method provided that the assumptions and methodology are initially declared. Our efforts toward the establishment of a MCID will rely on the establishment of specific external criteria based on the symptoms of the patient and treatment intervention being evaluated.     

Dépistage organisé du cancer colorectal

Acta Endoscopica - C’est un test de sélection. C’est un outil important de communication et d’information, c’est dire si elle doit être connue, comprise et bien...     

Endoscopic T-tube placement in the management of lye-induced esophageal perforation: Case report of a safe treatment strategy

Esophageal perforation is associated with a significant risk of morbidity and mortality. We report herein a case of lye-induced esophageal perforation managed successfully by employing endoscopic T-tube placement with a successful outcome.     

Program Directors' Views of the Effect of Managed Care on Substance Abuse Programs in Southern California

This article reports the results of semi-structured interviews with substance abuse treatment (SAT) program directors (PDs) regarding the ways SAT is being influenced by managed care (MC), plans for future SAT, and strategies for decreasing costs of care. It compares findings to an earlier survey of 50 SAT PDs.

Interviews were conducted in 20 SAT programs to gather information about treatment delivery since the advent of MC, including PD responsibilities, funding source, treatment intensity, location, duration, and methods of treatment. Open-ended responses were used to gather information about current and future plans in providing SAT, and awareness of new types of treatment being planned by organizations impacted by MC.

PDs reported changes in SAT secondary to MC such as decreased treatment length, limiting of inpatient and outpatient services, and delayed treatment secondary to benefit determination. Political and economic constraints were seen as barriers to providing adequate and effective services. SAT being subsumed by mental health was viewed as problematic along with an emerging split between alcohol abuse and drug treatment. A positive emerging treatment trend was the development of targeted programs for special need groups.

PDs revealed a variety of strategies that have promoted necessary adaptations to economic and political influences within the structure of managed behavioral care. Strategies such as varying treatment length, modality, and subspecialty care reflected necessary adaptations to diverse market needs.

Managed care continues to have a tremendous impact on the delivery of SAT services. While MC has helped to contain costs, negative outcomes are decreased availability of appropriate care and overtaxing of units that have survived MC cut backs. However, special need programs have allowed SAT programs to specialize, expand, and even flourish in today's competitive SAT market. Interviews with PDs reinforced the need for maintaining quality and diversified SAT services in today's MC environment.     

Outcomes and presurgery correlates of lumbar discectomy in Utah Workers' Compensation patients

Background contextLumbar discectomy is the most common type of back surgery performed in the United States. Outcomes after this procedure can be variable and it appears that Workers' Compensation patients might be at increased risk for poor outcomes.PurposeTo examine long-term multidimensional outcomes of lumbar discectomy within a cohort of Workers' Compensation patients from Utah and identify presurgical biopsychosocial factors related to poor outcomes.Study design/settingA retrospective cohort study consisting of a review of presurgical medical records and assessment of patient outcomes via a telephone survey. Outcomes were assessed at least 2 years postsurgery.Patient sampleA consecutive sample of 271 workers from Utah who underwent lumbar discectomy from 1994 to 1999. A total of 134 patients were surveyed at the time of follow-up.Outcome measuresPatient satisfaction, Roland-Morris Disability Questionnaire, SF-36v2, and Stauffer-Coventry Index.MethodsA retrospective review of presurgical biopsychosocial variables and outcome assessment via telephone survey was conducted.ResultsWork disability rate for the cohort was 12.7% (17/134). Analysis of patient satisfaction, back pain-related dysfunction, and the Short-Form Health Survey-36 subscales indicated approximately 25% of patients experienced poor outcomes. Older age, number of comorbid health conditions, assigned case manager, litigation, and time delay from injury to surgery were consistently statistically significant predictors (p<.05) of poor outcomes.ConclusionsResults of this study suggest that compensated back surgery patients are at greater risk for poor lumbar discectomy outcomes than noncompensation patients. Presurgery correlates of poor outcomes may be useful in identifying high-risk compensation patients.     

Reduced oligomeric and vascular amyloid-β following immunization of TgCRND8 mice with an Alzheimer's DNA vaccine

Immunization with amyloid-β (Aβ) peptide reduces amyloid load in animal studies and in humans; however clinical trials resulted in the development of a pro-inflammatory cellular response to Aβ. Apoptosis has been employed to stimulate humoral and Th2-biased cellular immune responses. Thus, we sought to investigate whether immunization using a DNA vaccine encoding Aβ in conjunction with an attenuated caspase generates therapeutically effective antibodies. Plasmids encoding Aβ and an attenuated caspase were less effective in reducing amyloid pathology than those encoding Aβ alone. Moreover, use of Aβ with an Arctic mutation (E22G) as an immunogen was less effective than wild-type Aβ in terms of improvements in pathology. Low levels of IgG and IgM were generated in response to immunization with a plasmid encoding wild-type Aβ. These antibodies decreased plaque load by as much as 36 ± 8% and insoluble Aβ42 levels by 56 ± 3%. Clearance of Aβ was most effective when antibodies were directed against N-terminal epitopes of Aβ. Moreover, immunization reduced CAA by as much as 69 ± 12% in TgCRND8 mice. Finally, high-molecular-weight oligomers and Aβ trimers were significantly reduced with immunization. Thus, immunization with a plasmid encoding Aβ alone drives an attenuated immune response that is sufficient to clear amyloid pathology in a mouse model of Alzheimer's disease.