Long-term outcomes of slipped capital femoral epiphysis treated with in situ pinning.

PURPOSE: Slipped capital femoral epiphysis (SCFE) is the commonest hip disorder in adolescents. In situ pinning is commonly performed, yet lately there has been an increase in procedures with open reduction and internal fixation. These procedures, however, are technically demanding with relatively high complication rates and unknown long-term outcomes. Nevertheless, reports on long-term results of in situ fixation are not equivocal. This study evaluates the possible higher risk of worse outcome after in situ pinning of SCFE. METHODS: All patients treated for SCFE with in situ fixation between 1980 and 2002 in four different hospitals were asked to participate. Patients were divided into three groups, based on severity of the slip. Patients were invited to the outpatient clinic for physical examination and X-rays, and to fill out the questionnaires HOOS, EQ5D, and SF36. ANOVA and chi-squared tests were used to analyze differences between groups. RESULTS: Sixty-one patients with 78 slips filled out the questionnaires. Patients with severe slips had worse scores on HOOS, EQ5D, and SF36. 75 % of patients with severe slips had severe osteoarthritis, compared to 2 % of mild and 11 % of moderate slips. CONCLUSION: Hips with mild and moderate SCFE generally had good functional and radiological outcome at a mean follow-up of 18 years, and for these hips there seems to be no indication for open procedures. However, severe slips have a significantly worse outcome, and open reduction and internal fixation could therefore be considered.

Hyperplasia of rib and vertebra, associated with infiltrating lipoma: a rare case of focal overgrowth.

PURPOSE: Syndromes with focal overgrowth are rare and diagnosis is difficult because manifestations are highly variable and symptoms overlap between syndromes. Diagnosis depends on clinical history, physical examination, and radiologic and histologic findings. This report describes a case of focal overgrowth of the left seventh rib and half of the adjacent thoracic vertebra, with overlying infiltrating lipoma. METHODS: A 13-year-old boy presented with an asymptomatic chest wall mass caused by enlargement of the seventh rib and an overlying soft-tissue mass accompanied by enlargement of half of the seventh thoracic vertebra. MRI showed infiltration of lipomatous tissue in the muscles, but no interfascicular accumulation of adipose tissue in the thoracic spinal nerve. RESULTS: A similar case was presented in 1985 but without MR imaging. CONCLUSION: We report on a second case of focal overgrowth of a rib and half of the adjacent vertebra, and overlying lipoma. In addition to the first case, we present MR images demonstrating infiltration of the adipose tissue.

Gene therapy for the treatment of hip prosthesis loosening: adverse events in a phase 1 clinical study.

Revision surgery for loosened hip prostheses is a heavy burden for elderly patients with comorbidity. As an alternative to surgery we performed a study to stabilize the prosthesis by percutaneous cement injection after removing inflammatory tissue with an intraarticular virus-directed enzyme prodrug approach. Twelve elderly patients with debilitating pain from a loosened hip prosthesis were included in a phase 1 dose-escalating clinical study. The patients were admitted to the hospital for 10 days for an intraarticular vector and prodrug injection, and subsequently for a percutaneous bone cement injection. This paper reports the adverse and serious adverse events of the study. After prodrug injection 9 of 12 patients had gastrointestinal adverse events (nausea, vomiting, and diarrhea), and 8 patients had hepatic adverse events (rise in aspartate aminotransferase and alanine aminotransferase). Five patients developed anemia (World Health Organization grade 1 or 2) from hematomas after cement injection. There were four serious adverse events in the first 6 months after vector injection, but these were not related to gene therapy as judged by an independent safety committee. There was no dose-limiting toxicity. However, the extensive comorbidity in these patients makes it difficult to fully establish the safety of the approach in this small and heterogeneous patient population.

Gene therapy and cement injection for restabilization of loosened hip prostheses.

Loosening of orthopedic hip prostheses is an increasing health problem. In elderly patients with comorbidity,revision surgery may lead to high mortality rates. A less invasive surgical technique is therefore required to reduce these patient risks. To this end a percutaneous gene therapy approach was designed to destroy the periprosthetic loosening membrane, and enable refixing of the hip prosthesis with percutaneous bone cement injections under radiological guidance. In this phase 1/2 dose-escalating gene therapy clinical trial, 12 patients were treated. Toxicity and hip function variables were monitored up to 6 months posttreatment. All patients completed the study and no dose-limiting toxicity was observed. Improvement in walking distance, independence,and pain was demonstrated particularly in patients receiving 3 x 10(10) and 1 x 10(11) viral particles. Taken together, these data show that this gene therapy approach targeted at the interface membrane around a loosened hip prosthesis is a feasible treatment option for elderly patients for whom surgical intervention is not appropriate.

Optimization of short-term transgene expression by sodium butyrate and ubiquitous chromatin opening elements (UCOEs).

BACKGROUND: Predictable and adequate transgene expression is essential for clinical gene therapy. Several studies have focused on optimization of transgene expression. In this study the effect of sodium butyrate (NaB) and a ubiquitous chromatin opening element (UCOE) on short-term gene expression after adenovirus-mediated gene transfer in fibroblastic interface cells from periprosthetic tissue in loosened orthopedic implants is investigated. METHODS: Cultures of diploid human interface cells from four patients were infected with an adenovirus type-5 vector that carries the luciferase gene driven by the cytomegalovirus (CMV) promoter as a reporter. In addition, viruses with a UCOE were evaluated. Twenty-four hours after infection NaB was added in concentrations of 0 to 9 mM. Luciferase activity was tested after a further 24 h. RESULTS: NaB in a concentration of 6 mM caused a 7- to 16-fold increase in reporter gene expression compared to control condition. There was no difference in reporter gene expression when cells were infected with Ad.1.5UCOE-CMV.Luc compared to Ad.CMV.Luc. A combination of NaB and a UCOE had no advantage over NaB alone. CONCLUSIONS: Addition of NaB results in a marked increase in transgene expression in cultured cells. This would allow the enhancement of the expression of the transgene, without requiring a higher vector dose. Butyrate administration could not be substituted by inclusion of UCOEs in the vector. It remains to be established whether the effective concentrations of butyrate can be obtained in vivo.

Arthrography in loosened hip prostheses. Assessment of possibilities for intra-articular therapy.

BACKGROUND: Loosening is a major complication in prosthesis surgery. Less invasive alternatives to revision surgery are required to prevent and treat prosthesis loosening. Some experimental therapies investigating alternative treatments exploit the intra-articular space as a route of administration. For efficient, local delivery of therapeutic agents a contained joint space is required. Furthermore, the volume of the joint space determines the concentration of the therapeutic ingredient in the joint. METHODS: A retrospective analysis of 221 hip arthrograms performed between 1994 and 2004 for diagnosis of prosthesis loosening was performed. All arthrograms were studied for leakage of contrast medium and the volume of injected contrast medium. RESULTS: There was a contained joint in 164 arthrograms (74%). The volume in these hips was 31+/-12.7 ml. Male patients had a larger joint volume than female patients (P=0.019). There was no difference in containment and joint volume between hips with a primary and with a revised prosthesis. CONCLUSIONS: For successful intra-articular therapy it is necessary that the injected agent remains in the jointspace. As leakage of contrast medium was shown in about a quarter of hips, this study shows that an arthrogram may be useful in the inclusion procedure for intra-articular studies to determine containment of the joint and also the volume that can be injected.

Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954.

BACKGROUND: Loosening is a major complication in prosthesis surgery. To stabilize loosened orthopedic implants, the interface tissue surrounding the implant must be removed. As an alternative to manual removal, we explored the possibility of removing the tissue by gene-directed enzyme prodrug therapy. In the current study we investigated whether interface cells can be transduced by an HAdV-5 vector carrying the E.coli-derived nitroreductase gene and sensitized to the prodrug CB1954. METHODS: The gene transfer efficiency into cultures of diploid human interface cells was tested by exposing these cells to various concentrations of Ad.CMV.LacZ. Subsequently, we studied the susceptibility of cells to the NTR/CB1954 combination. RESULTS: X-gal staining of the Ad.CMV.LacZ-transduced cell cultures revealed that, at 200 plaque-forming units (pfu)/cell, 74% of the cells expressed the LacZ gene. Infection with an NTR construct in interface cell lines resulted in a 60-fold sensitization to the prodrug CB1954. In addition we observed that iotrolan (Isovist) contrast medium had no effect on viability of the cells. However, the presence of the contrast medium completely inhibited adenovirus-mediated gene transfer. CONCLUSIONS: From these data we conclude that HAdV-5-based vectors carrying nitroreductase can be used to sensitize interface tissue. Instead of contrast medium the clinical protocol will use an alternative visualization procedure.