Gene therapy of Osteosarcoma : Preclinical studies with adenoviral vectors and adenoviral oncolysis

Wuisman, P.I.J.M. [Promotor]Beusechem, V.W. van [Copromotor]Gerritsen, W.R. [Copromotor

Intravenous administration of the conditionally replicative adenovirus Ad5-Delta24RGD induces regression of osteosarcoma lung metastases

<p>Abstract</p> <p>Metastatic osteosarcoma (OS) has a very poor prognosis. New treatments are therefore wanted. The conditionally replicative adenovirus Ad5-Δ24RGD has shown promising anti-tumor effects on local cancers, including OS. The purpose of this study was to determine whether intravenous administration of Ad5-Δ24RGD could suppress growth of human OS lung metastases. Mice bearing SaOs-lm7 OS lung metastases were treated with Ad5-Δ24RGD at weeks 1, 2 and 3 or weeks 5, 6 and 7 after tumor cell injection. Virus treatment at weeks 1–3 did not cause a statistically significant effect on lung weight and total body weight. However, the number of macroscopic lung tumor nodules was reduced from a median of >158 in PBS-treated control mice to 58 in Ad5-Δ24RGD-treated mice (p = 0.15). Moreover, mice treated at weeks 5–7 showed a significantly reduced lung weight (decrease of tumor mass, p < 0.05), a significantly increased body weight gain (decrease of disease symptoms, p < 0.005) and a reduced number of macroscopic lung tumor nodules (median 60 versus > 149, p = 0.12) compared to PBS treated control animals. Adenovirus hexon expression was detected in lung tumor nodules at sacrifice three weeks after the last intravenous adenovirus administration, suggesting ongoing viral infection. These findings suggest that systemic administration of Ad5-Δ24RGD might be a promising new treatment strategy for metastatic osteosarcoma.</p

The effect of prophylactic cranial irradiation (PCI) for young stage III NSCLC patients: Subgroup analyses of the NVALT-11/DLCRG-02 study

Background: The NVALT-11/DLCRG-02 phase III study compared PCI to observation after chemo-radiotherapy (RT) for stage III NSCLC and showed a significant decrease in the cumulative incidence of symptomatic brain metastases (BM) in the PCI arm at two years (7% vs 27% [HR 0.23]). We here performed exploratory subgroup analyses. Methods: Two year cumulative incidence rates were calculated and competing risk regression, with death of any cause as competing risk, was used to examine the time to symptomatic BM in the following subgr

Active monitoring versus an abduction device for treatment of infants with centered dysplastic hips: study protocol for a randomized controlled trial (TReatment with Active Monitoring (TRAM)-Trial)

Background: Developmental Dysplasia of the Hip (DDH) is one of the most common pediatric orthopedic disorders, affecting 1-3% of all newborns. The optimal treatment of centered DDH is currently under debate. This randomized controlled trial aims to study the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH. Methods: This is a multicenter, parallel-group, open-label, non-inferiority randomized controlled trial studying the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH in fourteen hospitals in the Netherlands. In total, 800 infants with centered DDH (Graf IIa-/IIb/IIc), aged 10-16 weeks, will be randomly allocated to the active monitoring or abduction treatment group. Infants will be followed up until the age of 24 months. The primary outcome is the rate of normal hips, defined as an acetabular index lower than 25 degrees on an antero-posterior radiograph, at the age of 12 months. Secondary outcomes are the rate of normal hips at the age of 24 months, complications, time to hip normalization, the relation between baseline patient characteristics and the rate of normal hips, compliance, costs, cost-effectiveness, budget impact, health-related quality of life (HRQoL) of the infant, HRQoL of the parents/caregivers, and parent/caregiver satisfaction with the treatment protocol.Discussion: The outcomes of this randomized controlled trial will contribute to improving current care-as-usual for infants with centered DDH.Orthopaedics, Trauma Surgery and Rehabilitatio

Fibroma of Tendon Sheath Located within Kager's Triangle

The formation of a fibroma of the tendon sheath, a rare, slow-growing, benign tumor, usually occurs in the upper extremities of young adult males. We present an extremely rare case of a fibroma of the tendon sheath arising adjacent to the Achilles tendon within Kager's triangle in a 41-year-old female. The patient presented with progressive pain localized to the posterior aspect of the left ankle. Complete excision and histopathologic analysis of the fibroma were performed. The patient experienced an uneventful recovery after the intervention and had no evidence of recurrence after 3 months of follow-up. Fibroma of the tendon sheath should be included in the differential diagnosis when a patient presents with a painful soft tissue mass in Kager's triangle. (C) 2014 by the American College of Foot and Ankle Surgeons. All rights reserved

"Employability-miles" and worker employability awareness

This article studies the use and impact of a firm-sponsored training (Employability-miles) voucher scheme that aims to stimulate employees to develop a more active attitude toward their own employability. Using data from two surveys of the firm's workforce, we find that voucher use is related to various personality traits and personal characteristics. In particular, a worker's ambition, goal setting, and education level are positively related to voucher use. In addition, women and those with longer tenure spend their vouchers more often. Conversely, workers with a more positive self-image as well as those who are negatively reciprocal spend their vouchers less often. The negative relation between voucher use and negative reciprocity suggests that workers who are more negatively reciprocal perceive the voucher as an HR tool for outplacement. Further, we find that voucher use positively affects worker employability awareness and willingness to train. Remarkably, participation in non-voucher training shows little relation to personality traits. From a human resources perspective, this finding suggests that by employing a voucher scheme, the firm makes training participation more dependent on employee personality and individual characteristics instead of the human resources development strategy of the firm

A randomized crossover study of functional electrical stimulation during walking in spastic cerebral palsy: the FES on participation (FESPa) trial

Background: Spastic cerebral palsy is the most common cause of motor disability in children. It often leads to foot drop or equinus, interfering with walking. Ankle-foot orthoses (AFOs) are commonly used in these cases. However, AFOs can be too restrictive for mildly impaired patients. Functional electrical stimulation (FES) of the ankle-dorsiflexors is an alternative treatment as it could function as a dynamic functional orthosis. Despite previous research, high level evidence on the effects of FES on activities and participation in daily life is missing. The primary aim of this study is to evaluate whether FES improves the activity and participation level in daily life according to patients, and the secondary aim is to provide evidence of the effect of FES at the level of body functions and activities. Furthermore, we aim to collect relevant information for decisions on its clinical implementation.Methods: A randomized crossover trial will be performed on 25 children with unilateral spastic cerebral palsy. Patients aged between 4 and 18 years, with Gross Motor Functioning Classification System level I or II and unilateral foot drop of central origin, currently treated with AFO or adapted shoes, will be included. All participants will undergo twelve weeks of conventional treatment (AFO/adapted shoes) and 12 weeks of FES treatment, separated by a six-week washout-phase. FES treatment consists of wearing the WalkAide (R) device, with surface electrodes stimulating the peroneal nerve during swing phase of gait. For the primary objective, the Goal Attainment Scale is used to test whether FES improves activities and participation in daily life. The secondary objective is to prove whether FES is effective at the level of body functions and structures, and activities, including ankle kinematics and kinetics measured during 3D-gait analysis and questionnaire-based frequency of falling. The tertiary objective is to collect relevant information for clinical implementation, including acceptability using the device log file and side effect registration, cost-effectiveness based on quality adjusted life years (QALYs) and clinical characteristics for patient selection.Discussion: We anticipate that the results of this study will allow evidence-based use of FES during walking in children with unilateral spastic cerebral palsy