Written language achievement in children and adolescents with neurofibromatosis type 1 and Plexiform Neurofibromas.

Neurofibromatosis type 1 (NF1) is associated with below average writing achievement. However, little is known about specific aspects of written language impacted by NF1, changes in writing over time, and associations between cognitive aspects of the NF1 phenotype and writing. At three timepoints over six years, children with NF1 and plexiform neurofibromas (PNs) completed Woodcock-Johnson tests of writing mechanics (Spelling, Punctuation & Capitalization, handwriting), written expression of ideas (Writing Samples), writing speed (Writing Fluency), and tests of general cognitive ability, executive function, memory, and attention. Children (N = 76, mean age = 12.8 ± 3.4 years) completed at least one baseline writing subtest. Overall writing scores were in the Average range (M = 93.4, SD = 17.4), but lower than population norms (p = 0.002). Scores were highest on Writing Samples (M = 95.2, SD = 17.3), and lowest for Punctuation & Capitalization (M = 87.9, SD = 18.8, p = 0.034). Writing scores were mostly stable over time. Nonverbal reasoning was related to some tests of writing mechanics and written expression of ideas. Short-term memory and inattention explained additional variance in Writing Samples and Spelling. Poor handwriting was associated with writing content beyond the impact of cognitive factors. Children with NF1 and PNs may benefit from early screening and writing support. Interventions should address the contribution of both cognitive and handwriting difficulties in written language.

Longitudinal association between executive function and academic achievement in children with neurofibromatosis type 1 and plexiform neurofibromas.

OBJECTIVE: To examine how executive functioning (EF) relates to academic achievement longitudinally in children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and whether age at baseline moderates this relationship. METHOD: Participants included 88 children with NF1 and PNs (ages 6-18 years old, M = 12.05, SD = 3.62, 50 males) enrolled in a natural history study. Neuropsychological assessments were administered three times over 6 years. EF (working memory, inhibitory control, cognitive flexibility, and attention) was assessed by performance-based (PB) and parent-reported (PR) measures. Multilevel growth modeling was used to examine how EF at baseline related to initial levels and changes in broad math, reading, and writing across time, controlling for demographic variables. RESULTS: The relationship between EF and academic achievement varied across EF and academic domains. Cognitive flexibility (PB) uniquely explained more variances in initial math, reading, and writing scores; working memory (PB) uniquely explained more variances in initial levels of reading and writing. The associations between EF and academic achievement tended to remain consistent across age groups with one exception: Lower initial levels of inhibitory control (PR) were related to a greater decline in reading scores. This pattern was more evident among younger (versus older) children. CONCLUSIONS: Findings emphasize the heterogeneous nature of academic development in NF1 and that EF skills could help explain the within-group variability in this population. Routine cognitive/academic monitoring via comprehensive assessments and early targeted treatments consisting of medication and/or systematic cognitive interventions are important to evaluate for improving academic performance in children with NF1 and PNs.

Demographic and Disease-Related Predictors of Socioemotional Development in Children with Neurofibromatosis Type 1 and Plexiform Neurofibromas: An Exploratory Study.

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) have a higher risk for socioemotional problems. The current study aims to identify the socioemotional developmental pattern and its predictors across childhood and adolescence in individuals with NF1 and PNs. Participants included 88 children with NF1 and PNs (aged 6-18 years old, M = 12.05, SD = 3.62, 57% male) in a natural history study. Neuropsychological assessments were administered three times over six years. There are large variabilities in socioemotional development in the study participants. Developmental patterns varied across socioemotional domains, respondent type (parent-report [PR] vs. child-report [CR]), demographic factors, and NF1 disease-related factors. For instance, lower parental education was associated with a greater decline in internalizing problems (PR) but a greater increase in school disconnectedness (CR) over time. Non-White (vs. White) children were more likely to experience increased adaptive skills (PR) but decreased personal adjustment (CR). Children with more visible tumors experienced a greater decrease in school disconnectedness (CR). Children with more NF1 complications experienced a greater decrease in externalizing problems (PR). These findings indicate the necessity of using multi-informants and investigating subdomains of socioemotional functions. They also highlight the importance of developing individualized approaches to patient care and interventions.

Verbal learning and memory in youth with neurofibromatosis type 1 and plexiform neurofibromas: Relationships with disease severity.

AIM: To provide a comprehensive characterization of verbal learning and memory (VLM) abilities in youth with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and to evaluate disease severity as a predictor of VLM functioning over time. METHOD: As part of a longitudinal natural history study, youth with NF1 and PNs were administered repeat neuropsychological assessments, including measures of VLM and ratings of NF1 disease severity completed by a medical professional. This sub-study analyzed data from 89 patients (M age baseline = 13.1, SD = 4.3 years, range 6-24 years) who had completed tests of VLM abilities and verbal attention at either baseline and/or 36 months. RESULTS: VLM scores across the sample fell predominantly within the average range of functioning at both time points. However, relative to peers with mild NF1 disease severity, youth with moderate/severe NF1 disease showed lower functioning across multiple VLM domains at 36 months, even after controlling for the effects of verbal attention. INTERPRETATION: Exclusive use of overall domain scores does not fully characterize VLM functioning in youth with NF1 and PNs. Additionally, children and adolescents with more severe NF1 disease should be monitored more closely for verbal memory challenges and targeted for interventions.

Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: growth analysis of plexiform neurofibromas and distinct nodular lesions.

BACKGROUND: Understanding the natural history of non-malignant peripheral nerve sheath tumors (PNSTs) in neurofibromatosis type 1 (NF1) is critical to optimal clinical care and the development of meaningful clinical trials. METHODS: We longitudinally analyzed growth of plexiform neurofibromas (PNs) and of PNSTs with distinct nodular appearance (distinct nodular lesions [DNLs]) using volumetric MRI analysis in patients enrolled on a natural history study (NCT00924196). RESULTS: DNLs were observed in 58/122 (45.6%) patients (median 2 DNLs/patient). In DNLs that developed during follow-up, median age of development was 17 years. A moderate negative correlation was observed between the estimated PN growth rate and patients' age at initial MRI (Spearman's r [95% CI]: -0.60 [-0.73, -0.43], n = 70), whereas only a weak correlation was observed for DNLs (Spearman's r [95% CI]: -0.25 [-0.47, 0.004]; n = 61). We observed a moderate negative correlation between tumor growth rate and baseline tumor volume for PNs and DNLs (Spearman's r [95% CI]: -0.52 [-0.67, -0.32] and -0.61 [-0.75, -0.42], respectively). Spontaneous tumor volume reduction was observed in 10 PNs and 7 DNLs (median decrease per year, 3.6% and 7.3%, respectively). CONCLUSION: We corroborate previously described findings that most rapidly growing PNs are observed in young children. DNLs tend to develop later in life and their growth is minimally age related. Distinct growth characteristics of PNs and DNLs suggest that these lesions have a different biology and may require different clinical management and clinical trial design. In a subset of PNs and DNLs, slow spontaneous regression in tumor volume was seen.

Predictors of cognitive development in children with neurofibromatosis type 1 and plexiform neurofibromas.

AIM: To describe the cognitive development of children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas, and identify predictors of cognitive development. METHOD: Participants included 88 children with NF1 and plexiform neurofibromas (50 males, 38 females, aged 6-18y, mean=12y, SD=3y 7mo) on a natural history study at the National Cancer Institute. Neuropsychological assessments (e.g. IQ, academic achievement, attention, and executive functioning) were administered three times over 6 years. RESULTS: Relative to normative peers, the total sample of children with NF1 and plexiform neurofibromas demonstrated significantly lower scores in most cognitive domains and decreasing z-scores over time in math, writing, inhibitory control, and working memory. Children who had parents with (vs without) NF1 were more likely to experience decreased z-scores in performance IQ, reading, writing, attention, and working memory. Higher (vs lower) parental education was related to higher levels of IQ, math, reading, and cognitive flexibility and a slower decrease in math z-scores. Children's sex and the number of NF1 disease-related complications were not related to most cognitive outcomes. INTERPRETATION: Children with NF1 and plexiform neurofibromas are at high risk for cognitive difficulties and declining z-scores in various domains of cognitive functioning over time. The findings highlight the need for a better understanding of the within-group differences in these children and their need for individualized educational plans. WHAT THIS PAPER ADDS: Math, writing, inhibitory control, and working memory scores decreased over time. The proportion of children with clinically significant cognitive deficits increased over time. Parental neurofibromatosis type 1 and low education were related to greater cognitive difficulties in children.

Cediranib phase-II study in children with metastatic alveolar soft-part sarcoma (ASPS).

BACKGROUND: Alveolar soft-part sarcoma (ASPS), a rare vascular sarcoma with a clinically indolent course, frequently presents with metastases. Vascular endothelial growth factor (VEGF) is a promising therapeutic target. In a phase-II trial of the VEGF receptor inhibitor cediranib for adults with ASPS, the partial response (PR) rate (response evaluation criteria in solid tumors [RECIST] v1.0) was 35% (15/43; 95% confidence interval: 21-51%). We evaluated cediranib in the pediatric population. PROCEDURE: Patients <16 years old with metastatic, unresectable ASPS received cediranib at the pediatric maximum tolerated dose of 12 mg/m2 (≈70% of the fixed adult phase-II dose orally daily). Tumor response was assessed every two cycles (RECIST v1.0). A Simon two-stage optimal design (target response rate 35%, rule out 5%) was used. RESULTS: Seven patients (four females), with a median age of 13 years, (range 9-15), were enrolled on stage 1. The most frequent grade 2 or 3 adverse events were neutropenia, diarrhea, hypertension, fatigue, and proteinuria. The best response was stable disease (SD) (median cycle number = 34). Three patients were removed from the study treatment for disease progression (cycles 4, 5, and 36). Five of seven patients had SD for ≥14 months. Two patients with SD remain on study (34-57+ cycles). CONCLUSIONS: Cediranib did not reach the target response rate in this small pediatric cohort, in contrast to the adult 35% PR rate. The pediatric dosing was 30% lower compared to the adult dosing, which may have contributed to response differences. Prolonged SD was observed in five patients, but given the indolent nature of ASPS, SD cannot be clearly attributed to cediranib. Cediranib has an acceptable safety profile.

Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1.

Background: Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN-related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN-related morbidity. Methods: This is a retrospective review of patients enrolled on the NCI NF1 natural history study with ≥7 years of data available. Morbidities including pain, motor dysfunction, vision loss, and PN-related surgery were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume. Results: Forty-one patients (median age at baseline 8 y) with 57 PN were included. At baseline, 40 PN had at least 1 PN-associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%; 95% CI: 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n = 11) had larger volumes compared with those that did not (median difference 461 mL; 95% CI: 66.9, 820). Conclusions: Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN-associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes.

Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas.

Background: There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). Methods: PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1‒related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (≥20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Results: Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). Conclusions: In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status.

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors.

BACKGROUND: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. PROCEDURE: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. RESULTS: Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. CONCLUSIONS: The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed.

Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.

BACKGROUND: Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. PROCEDURE: Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. RESULTS: Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. CONCLUSIONS: Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN.

Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group.

BACKGROUND: The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies. PROCEDURE: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2) /dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity. RESULTS: Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m(2) /dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m(2) and the median half-life was 4.7 hr. At steady state on 300 mg/m(2) /dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed. CONCLUSIONS: Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 2 days schedule at 300 mg/m(2) /dose.

A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. PATIENTS AND METHODS: Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m(2)/d resulted in de-escalation to 8 mg/m(2)/d and subsequent re-escalation to 12 and 17 mg/m(2)/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. RESULTS: Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m(2)/d. Subsequently, 8 mg/m(2)/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m(2)/d; one had DLT (grade 3 diarrhea). At 17 mg/m(2)/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non-dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m(2)/d (adult fixed dose equivalent, 20 mg). At 12 mg/m(2)/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. CONCLUSION: The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m(2)/d administered orally, once daily, continuously. A phase II study is in development.

Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors.

PURPOSE: To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes. METHODS: Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75-250 mg/m(2)/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed. RESULTS: ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t (1/2) of 5.1 h. The apparent clearance was 33 ml/min/m(2) and was age-independent. The AUC(0-infinity) increased in proportion to the dose, and at 200 mg/m(2) the median AUC(0-infinity) was 91 mcg h/ml and the C (ave) was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3-5 h after the dose. The glucuronide:sulfate molar AUC(0-infinity) ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC(0-infinity) was higher in patients experiencing dose-limiting toxicity. CONCLUSIONS: Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.

Phase II trial of ixabepilone administered daily for five days in children and young adults with refractory solid tumors: a report from the children's oncology group.

PURPOSE: Ixabepilone is a microtubule-stabilizing agent with activity in adult solid tumors and in pediatric tumor xenograft models that are resistant to paclitaxel. The maximum tolerated dose on the daily-for-5-days i.v. schedule was 6 mg/m(2)/dose in adults and 8 mg/m(2)/dose in children, and the primary dose-limiting toxicity (DLT) was neutropenia. This study aimed to determine the response rate to ixabepilone in six solid tumor strata in children and young adults. EXPERIMENTAL DESIGN: We conducted a phase II trial of ixabepilone (8 mg/m(2)/dose for 5 days every 21 days) using a two-stage design in taxane-naïve children and young adults with treatment-refractory, measurable rhabdomyosarcoma, Ewing sarcoma family tumors, osteosarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor, neuroblastoma, and Wilms tumor. RESULTS: Sixty-one eligible patients (36 male) were enrolled. Median (range) age was 13 years (range, 3-36). Fifty-nine patients were fully evaluable for toxicity and response. DLTs, most commonly myelosuppression, occurred in 11 patients (15% incidence in 3-18 years old and 33% in 19-36 years old; P = 0.2) during cycle 1. The median (range) number of cycles was 2 (range, 1-38). No partial or complete responses (response evaluation criteria in solid tumors) were observed. Seven patients received >or=3 cycles, and two had prolonged stable disease (Wilms' tumor, 38 cycles; synovial sarcoma, 8 cycles). CONCLUSIONS: Ixabepilone at 8 mg/m(2)/dose daily for 5 days was tolerable in children and adolescents, but did not show evidence of clinical activity in the childhood solid tumors studied.

Autoimmunity in retinal degeneration: autoimmune retinopathy and age-related macular degeneration.

Autoantibody production is associated with a variety of ocular disorders, including autoimmune retinopathy (AIR) and age-related macular degeneration (AMD). A breakdown of immunologic tolerance (ocular immune privilege), including the blood-retinal barrier, anti-immune and anti-inflammatory proteins, and anterior chamber-associated immune deviation may play important roles in these disorders. Although the exact triggers for ocular autoimmunity are unknown, autoimmune targeting of retinal tissue is clearly associated with and may contribute to the pathogenesis of both AIR and AMD. Autoantibody production has long been associated with AIR, a collection of disorders that includes cancer-associated retinopathy, melanoma-associated retinopathy and non-paraneoplastic autoimmune retinopathy. A growing body of evidence indicates that AMD pathogenesis, too, involves ocular inflammation and autoimmunity. Identification and quantification of autoantibodies produced in patients with AIR and AMD may assist with diagnosis, prognosis, and choice of treatments. Animal models that allow investigation of ocular autoimmunity will also be needed to better understand the disease processes and to develop novel therapies. In this review we discuss ocular immune privilege and potential mechanisms of autoimmunity in the eye. We describe how autoimmunity relates to the pathogenesis of AIR and AMD. We explain how the antigen microarray technique is used to detect autoantibodies in patient serum samples, and discuss how current animal models for AMD can be used to investigate autoimmune pathogenesis. Finally, we outline unanswered questions and exciting areas of future study related to autoimmune retinal degeneration.

Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors.

PURPOSE: The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents. PATIENTS AND METHODS: Patients >or= 2 and 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours. CONCLUSION: The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. EXPERIMENTAL DESIGN: Patients who were < or = 18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m(2)/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m(2)/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. RESULTS: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m(2)/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. CONCLUSION: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m(2)/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.

In vitro assays of angiogenesis for assessment of angiogenic and anti-angiogenic agents.

Blood vessels, either in insufficient numbers or in excess, contribute to the pathogenesis of many diseases. Agents that stimulate angiogenesis can improve blood flow in patients with ischemic diseases, whereas anti-angiogenic agents are used to treat disorders ranging from macular degeneration to cancer. In this review I describe in vitro assays that can be used to assess the activity of agents that affect angiogenesis. Means of quantifying endothelial cell matrix degradation, migration, proliferation, apoptosis and morphogenesis are discussed, as are embryoid body, aortic ring and metatarsal assays of vessel outgrowth. Strengths and limitations of these techniques are also addressed.