Visualizing inflammation activity in rheumatoid arthritis with Tc-99 m anti-CD4-mAb fragment scintigraphy.

PURPOSE: T-cell-located CD4 antigen represents one of the therapeutic targets in rheumatoid arthritis (RA). However, up to now there is no established imaging tool to visualize this target in vivo. The aim of our study was to assess the safety and tolerability of a technetium-99m labelled murine anti-human CD4 IgG1-Fab fragment ([(99m)Tc]-anti-CD4-Fab, [(99m)Tc]-EP1645) in patients with active synovitis due to RA, and to evaluate its potential as a marker of disease activity. METHODS: In the present phase I proof of principle study five patients with RA were examined. Planar scans of the whole body, hands, and feet were taken 30 min up to 24h after application of 550 ± 150 MBq [(99m)Tc]-anti-CD4-Fab, followed by visual analyses, comparison with clinical data in 68 joints per patient and semiquantitative analysis of hand and wrist joints. RESULTS: Neither infusion related adverse events nor adverse events during follow up were observed. No increase in human anti-murine antibody titres was seen. All patients had positive scans in almost 70% of clinically affected joints. Positive scans were also found in 8% of joints without evidence of swelling or tenderness. CONCLUSION: Scintigraphy with [(99m)Tc]-anti-CD4-Fab is a promising technique for evaluation of inflammatory activity in patients with RA, pre-therapeutical evaluation of CD4 status and therapy control. Tracer uptake in clinically inconspicuous joints strongly indicates diagnostic potential of [(99m)Tc]-anti-CD4-Fab. Whether this technique is eligible as a prognostic factor in RA needs to be analysed in further studies as well as the pathophysiological background of clinically affected joints lacking tracer uptake.

Initial clinical results of simultaneous 18F-FDG PET/MRI in comparison to 18F-FDG PET/CT in patients with head and neck cancer.

PURPOSE: The aim of this study was to evaluate the diagnostic capability of simultaneous (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI compared to (18)F-FDG PET/CT as well as their single components in head and neck cancer patients. METHODS: In a prospective study 17 patients underwent (18)F-FDG PET/CT for staging or follow-up and an additional (18)F-FDG PET/MRI scan with whole-body imaging and dedicated examination of the neck. MRI, CT and PET images as well as PET/MRI and PET/CT examinations were evaluated independently and in a blinded fashion by two reader groups. Results were compared with the reference standard (final diagnosis determined in consensus using all available data including histology and follow-up). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: A total of 23 malignant tumours were found with the reference standard. PET/CT showed a sensitivity of 82.7%, a specificity of 87.3%, a PPV of 73.2% and a NPV of 92.4%. Corresponding values for PET/MRI were 80.5, 88.2, 75.6 and 92.5%. No statistically significant difference in diagnostic capability could be found between PET/CT and PET/MRI. Evaluation of the PET part from PET/CT revealed highest sensitivity of 95.7%, and MRI showed best specificity of 96.4%. There was a high inter-rater agreement in all modalities (Cohen's kappa 0.61-0.82). CONCLUSION: PET/MRI of patients with head and neck cancer yielded good diagnostic capability, similar to PET/CT. Further studies on larger cohorts to prove these first results seem justified.

Implementation of the process of ethical review of improvement activities at the Children's Hospital at Westmead.

INTRODUCTION: Research in healthcare has long been very well regulated, but this is rarely the case for improvement activities. Improvement activities are activities which use data to assess the current situation to identify areas for improvement. Solutions are then developed and implemented, and later evaluated to measure their success and sustainability. There has been much discussion in the literature as to whether, like research activities, improvement activities should undergo independent ethical review. In fact, most healthcare organisations in Australia struggle with how best to manage improvement activities, despite the 2003 publication of the National Health and Medical Research Council guidelines on this subject. DISCUSSION: At The Children's Hospital at Westmead, the authors take the view supported by others that ethical review is necessary and so have developed a process which utilises the unique skills available in the Clinical Governance Unit to ensure improvement activities are reviewed for ethical considerations in an effective and efficient manner and implemented a database to approve, monitor and report on improvement activities. This has resulted in staff being increasingly satisfied with the turnaround time for approval of improvement activities they are undertaking as well as for the methodological support provided. The authors have experienced a dramatic increase in the number of improvement activities being recorded and ethically reviewed.

The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications.

Recently, new long-acting formulations of racemic methylphenidate (MPH: Ritalin LA, Metadate CD and Concerta) and amphetamine (AMP: Adderall XR) were developed and are now approved by the Food and Drug Administration (FDA). In addition, dexmethylphenidate (Focalin), the pharmacologically active d-threo enantiomer of MPH, also was approved by the FDA. In the initial phases of development, prototypes of these five new formulations were evaluated using the University of California, Irvine (UCI) Laboratory School Protocol (LSP), in which surrogate measures of efficacy are collected in highly controlled settings rather than clinical measures of effectiveness in the less-controlled, natural environments of home or school. The LSP studies were followed by large effectiveness and safety studies required for gaining FDA approval. These initial efficacy and side effect studies in the LSP provided missing information about the basic pharmacokinetic (PK) and pharmacodynamic (PD) properties of MPH and AMP and produced some new discoveries (i.e., acute tolerance) that were used to help design the final products. The final once-a-day formulations used different drug delivery systems to achieve long-acting efficacy (Ritalin LA, Metadate CD, Concerta, Adderall XR). All four drug delivery systems were based on two processes: first, a bolus delivery (BD) process to achieve rapid onset of efficacy (mg), and second, a controlled delivery (CD) process to achieve rates of delivery (mg/hr) or a delayed bolus (mg) to maintain efficacy. A theoretical approach was used to compare and contrast the new once-a day formulations of MPH by selecting total daily doses (mg/d) that would equate drug delivery by the first process (mg of the initial bolus) and the second process (mg/hr over specified time period). In addition to efficacy, applications of the LSP to measure common side effects related to eating and sleeping were described and discussed.