Neurobehavioral problems at age 2 years in children with prenatal opioid exposure.

OBJECTIVE: To evaluate factors associated with borderline/clinical range Child Behavior Checklist (CBCL) scores in opioid-exposed children. STUDY DESIGN: Retrospective study of 94 children with prenatal opioid exposure evaluated with the CBCL at age 2 years. RESULTS: Twenty-eight children (30%) had borderline/clinical findings on the CBCL, with 27% scoring borderline/clinical for Externalizing Problems. In the multivariable model, lower Bayley-III motor scores and discharge home with mother with safety plan were associated with borderline/clinical Externalizing Problems. Medication treatment for neonatal opioid withdrawal syndrome (NOWS) was associated with normal Externalizing Problems scores. Treatment with clonidine or phenobarbital was associated with scores in the normal range in all broadband CBCL measures. CONCLUSION: Specific factors are associated with behavioral and emotional challenges measured by borderline/clinical CBCL scores among opioid-exposed children.

Risk factors for near-miss events and safety incidents in pediatric radiation therapy.

BACKGROUND AND PURPOSE: Factors contributing to safety- or quality-related incidents (e.g. variances) in children are unknown. We identified clinical and RT treatment variables associated with risk for variances in a pediatric cohort. MATERIALS AND METHODS: Using our institution's incident learning system, 81 patients age ≤21 years old who experienced variances were compared to 191 pediatric patients without variances. Clinical and RT treatment variables were evaluated as potential predictors for variances using univariate and multivariate analyses. RESULTS: Variances were primarily documentation errors (n = 46, 57%) and were most commonly detected during treatment planning (n = 14, 21%). Treatment planning errors constituted the majority (n = 16 out of 29, 55%) of near-misses and safety incidents (NMSI), which excludes workflow incidents. Therapists reported the majority of variances (n = 50, 62%). Physician cross-coverage (OR = 2.1, 95% CI = 1.04-4.38) and 3D conformal RT (OR = 2.3, 95% CI = 1.11-4.69) increased variance risk. Conversely, age >14 years (OR = 0.5, 95% CI = 0.28-0.88) and diagnosis of abdominal tumor (OR = 0.2, 95% CI = 0.04-0.59) decreased variance risk. CONCLUSIONS: Variances in children occurred in early treatment phases, but were detected at later workflow stages. Quality measures should be implemented during early treatment phases with a focus on younger children and those cared for by cross-covering physicians.

Combined EphB2 receptor knockdown with radiation decreases cell viability and invasion in medulloblastoma.

BACKGROUND: Medulloblastoma is one of the most common types of pediatric brain tumor characterized by the subpopulation of cells that exhibit high invasive potential and radioresistant properties. In addition, dysregulated function and signaling by Eph family of receptors have been shown to impart pro-tumorigenic characteristics in this brain malignancy. In the current study, we investigated whether EphB2 knockdown in combination with radiation can alter invasiveness and decrease medulloblastoma tumor growth or viability in vitro. METHODS: The expression of EphB2 receptor was analyzed by immunohistochemistry and Western blotting. Microarray analysis and mRNA analysis was performed on medulloblastoma patient datasets and compared to the normal cerebellum. The radiosensitization effect following EphB2 knockdown was determined by clonogenic assay in human medulloblastoma cells. Effects of EphB2-siRNA in absence or presence of radiation on cell cycle distribution, cell viability, and invasion were analyzed by flow cytometry, MTT assay, trypan blue exclusion assay, xcelligence system, and Western blotting. RESULTS: We observed that EphB2 is expressed in both medulloblastoma cell lines and patient samples and its downregulation sensitized these cells to radiation as evident by decreased clonogenic survival fractions. EphB2 expression was also high across different medulloblastoma subgroups compared to normal cerebellum. The radiosensitization effect observed following EphB2 knockdown was in part mediated by enhanced G2/M cell cycle arrest. We also found that the combined approach of EphB2 knockdown and radiation exposure significantly reduced overall cell viability in medulloblastoma cells compared to control groups. Similar results were obtained in the xcelligence-based invasion assay. Western blot analysis also demonstrated changes in the protein expression of cell proliferation, cell survival, and invasion molecules in the combination group versus others. CONCLUSIONS: Overall, our findings indicate that specific targeting of EphB2 receptor in combination with radiation may serve as an effective therapeutic strategy in medulloblastoma. Future studies are warranted to test the efficacy of this approach in in vivo preclinical models.

Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model.

BACKGROUND: Members of the Eph/ephrin gene families act as key regulators of cerebellar development during embryogenesis. Aberrant signaling of Eph family of receptor tyrosine kinases and their ephrin ligands has also been implicated in human cancers. Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum. Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration. In the present study, we investigated the effects of genetic loss of ephrin-A5, EphA4, and EphA7 on the spatiotemporal development of medulloblastoma tumors in the context of the smoothened transgenic mouse model system. FINDINGS: Radiographic magnetic resonance imaging (MRI) was performed to monitor tumor growth in a genetically engineered mouse model of medulloblastoma. Tumor tissue was harvested to determine changes in the expression of phosphorylated Akt by Western blotting. This helped to establish a correlation between genotype and/or tumor size and survival. Our in vivo data establish that in ND2-SmoA1 transgenic mice, the homozygous deletion of ephrin-A5 resulted in a consistent pattern of tumor growth inhibition compared to their ephrin-A5 wild-type littermate controls, while the loss of EphA4/EphA7 failed to produce consistent effects versus EphA4/EphA7 wild-type mice. A positive correlation was evident between tumor size, p-Akt, and proliferating cell nuclear antigen (PCNA) expression in our transgenic mouse model system, regardless of genotype. CONCLUSIONS: Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.

Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.

The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased ß1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.

Trigeminal neuralgia treatment outcomes following Gamma Knife radiosurgery with a minimum 3-year follow-up.

OBJECTIVE: Effective short-term outcomes have been well documented for trigeminal neuralgia (TN) patients treated with Gamma Knife radiosurgery (GKRS) with reported success rates of 70-90 % with median follow-up intervals of 19-75 months. Fewer series, however, have described uniform long-term follow-up data. In this study, we report our long-term institutional outcomes in patients treated with GKRS after a minimum follow-up of 36 months. METHODS: Thirty-six consecutive patients with medically intractable TN received a median radiation dose of 45 Gy applied with a single 4-mm isocenter to the affected trigeminal nerve. Follow-up data were obtained by clinical examination and telephone questionnaire. Outcome results were categorized based on the Barrow Neurological Institute (BNI) pain scale with BNI I-III considered to be good outcomes and BNI IV-V considered as treatment failure. BNI facial numbness score was used to assess treatment complications. RESULTS: The incidence of early pain relief was high (80.5 %) and relief was noted in an average of 1.6 months after treatment. At minimum follow-up of 3 years, 67 % were pain free (BNI I) and 75 % had good treatment outcome. At a mean last follow-up of 69 months, 32 % were free from any pain and 63 % were free from severe pain. Bothersome posttreatment facial numbness was reported in 11 % of the patients. A statistically significant correlation was found between age and recurrence of any pain with age >70 predicting a more favorable outcome after radiosurgery. CONCLUSION: The success rate of GKRS for treatment of medically intractable TN declines over time with 32 % reporting ideal outcome and 63 % reporting good outcome. Patients older than age 70 are good candidates for radiosurgery. This data should help in setting realistic expectations for weighing the various available treatment options.

Robotic stereotactic body radiation therapy for elderly medically inoperable early-stage non-small cell lung cancer.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is being increasingly applied in the treatment of non-small cell lung cancer (NSCLC) because of its high local efficacy. This study aims to examine survival outcomes in elderly patients with inoperable stage I NSCLC treated with SBRT. METHODS: A total of 31 patients with single lesions treated with fractionated SBRT from 2008 to 2011 were retrospectively analyzed. A median prescribed dose of 48 Gy was delivered to the prescription isodose line, over a median of four treatments. The median biologically effective dose (BED) was 105.6 (range 37.50-180), and the median age was 73 (65-90 years). No patient received concurrent chemotherapy. RESULTS: With a median follow up of 13 months (range, 4-40 months), the actuarial median overall survival (OS) and progression-free survival (PFS) were 32 months, and 19 months, respectively. The actuarial median local control (LC) time was not reached. The survival outcomes at median follow up of 13 months were 80%, 68%, and 70% for LC, PFS, and OS, respectively. Univariate analysis revealed a BED of >100 Gy was associated with improved LC rates (P = 0.02), while squamous cell histology predicted for worse LC outcome at median follow up time of 13 months (P = 0.04). Increased tumor volume was a worse prognostic indicator of both LC and OS outcomes (P < 0.05). Finally, female gender was a better prognostic factor for OS than male gender (P = 0.006). There were no prognostic indicators of PFS that reached statistical significance. No acute or subacute high-grade toxicities were documented. CONCLUSION: SBRT is a safe, feasible, and effective treatment option for elderly patients with inoperable early stage NSCLC. BED, histology, and tumor size are predictors of local control, while tumor size and gender predict OS.