In vivo expression and survival of gene-modified T lymphocytes in rhesus monkeys.

Lymphocytes can be readily transduced with retroviral vectors and the gene-modified lymphocytes will stably express the inserted genes in vitro for long periods. As a prelude to studies in humans, we evaluated the survival of gene-modified T lymphocytes and the expression of the introduced genes in nonhuman primate T lymphocytes both in vitro and in vivo to determine if lymphocytes could be a potential cellular gene therapy vehicle. Rhesus peripheral blood T-lymphocytes and/or lymph node lymphocytes were transduced with a retroviral vector that contained a bacterial neomycin resistance (NeoR) gene or both NeoR and the human adenosine deaminase (hADA) genes. The cells were then selected for NeoR expression by growth in the neomycin analogue G418 and the autologous gene-modified T cells were reintroduced into the donor animals. T lymphocytes were periodically regrown from the blood and selected in G418. Gene-modified cells persisted in 1 animal for 727 days as detected by analysis for vector DNA by polymerase chain reaction (PCR). Evidence for expression of the human ADA or NeoR genes has also been detected up to 727 days after cell infusion. These findings suggest that gene-modified T lymphocytes can survive and circulate for long periods in vivo and can continue to express the introduced genes.

Evaluation of a total scalp electron irradiation technique.

A dosimetric evaluation of a total scalp electron-beam irradiation technique that uses six stationary fields was performed. The initial treatment plan specified a) that there be a 3-mm gap between abutted fields and b) that the field junctions be shifted 1 cm after 50% of the prescribed dose had been delivered. Dosimetric measurements were made at the scalp surface, scalp-skull interface, and the skull-brain interface in an anthropomorphic head phantom using both film and thermoluminescent dosimeters (TLD-100). The measurements showed that the initial technique yields areas of increased and decreased dose ranging from -50% to +70% in the region of the field junctions. To reduce regions of nonuniform dose, the treatment protocol was changed by eliminating the gap between the coronal borders of abutted fields and by increasing the field shift from 1 cm to 2 cm for all borders. Subsequent measurements showed that these changes in treatment protocol resulted in a significantly more uniform dose to the scalp and decreased variation of doses near field junctions (-10% to +50%).

SU-E-T-207: Flatness and Symmetry Threshold Detection Using Statistical Process Control.

PURPOSE: AAPM TG-142 guidelines state that beam uniformity (flatness and symmetry) should maintain a constancy of 1 % relative to baseline. The focus of this study is to determine if statistical process control (SPC) methodology using process control charts (PCC) of steering coil currents (SCC) can detect changes in beam uniformity prior to exceeding the 1% constancy criteria. METHODS: SCCs for the transverse and radial planes are adjusted such that a reproducibly useful photon or electron beam is available. Transverse and radial - positioning and angle SCC are routinely documented in the Morning Check file during daily warm-up. The 6 MV beam values for our linac were analyzed using average and range (Xbar/R) PCC. Using this data as a baseline, an experiment was performed in which each SCC was changed from its mean value (steps of 0.01 or 0.02 Ampere) while holding the other SCC constant. The effect on beam uniformity was measured using a beam scanning system. These experimental SCC values were plotted in the PCC to determine if they would exceed the predetermined limits. RESULTS: The change in SCC required to exceed the 1% constancy criteria was detected by the PCC for 3 out of the 4 steering coils. The reliability of the result in the one coil not detected (transverse position coil) is questionable because the SCC slowly drifted during the experiment (0.05 A) regardless of the servo control setting. CONCLUSIONS: X-bar/R charts of SCC can detect exceptional variation prior to exceeding the beam uniformity criteria set forth in AAPM TG-142. The high level of PCC sensitivity to change may result in an alarm when in fact minimal change in beam uniformity has occurred. Further study is needed to determine if a combination of individual SCC alarms would reduce the false positive rate for beam uniformity intervention. This project was supoorted by a grant from Varian Medical Systems, Inc.

SU-E-T-205: MLC Predictive Maintenance Using Statistical Process Control Analysis.

PURPOSE: MLC failure increases accelerator downtime and negatively affects the clinic treatment delivery schedule. This study investigates the use of Statistical Process Control (SPC), a modern quality control methodology, to retrospectively evaluate MLC performance data thereby predicting the impending failure of individual MLC leaves. METHODS: SPC, a methodology which detects exceptional variability in a process, was used to analyze MLC leaf velocity data. A MLC velocity test is performed weekly on all leaves during morning QA. The leaves sweep 15 cm across the radiation field with the gantry pointing down. The leaf speed is analyzed from the generated dynalog file using quality assurance software. MLC leaf speeds in which a known motor failure occurred (8) and those in which no motor replacement was performed (11) were retrospectively evaluated for a 71 week period. SPC individual and moving range (I/MR) charts were used in the analysis. The I/MR chart limits were calculated using the first twenty weeks of data and set at 3 standard deviations from the mean. RESULTS: The MLCs in which a motor failure occurred followed two general trends: (a) no data indicating a change in leaf speed prior to failure (5 of 8) and (b) a series of data points exceeding the limit prior to motor failure (3 of 8). I/MR charts for a high percentage (8 of 11) of the non-replaced MLC motors indicated that only a single point exceeded the limit. These single point excesses were deemed false positives. CONCLUSIONS: SPC analysis using MLC performance data may be helpful in detecting a significant percentage of impending failures of MLC motors. The ability to detect MLC failure may depend on the method of failure (i.e. gradual or catastrophic). Further study is needed to determine if increasing the sampling frequency could increase reliability. Project was support by a grant from Varian Medical Systems, Inc.

The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To recommend the appropriate use of oral ganciclovir as an alternative to intravenous (i.v.) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS. OPTIONS: i.v. infusion of ganciclovir and foscarnet have been the only approved choices for maintenance therapy until the introduction of oral ganciclovir. OUTCOMES: Ease of administering maintenance therapy and improved quality of life for patients with AIDS. VALUES: The medical advisory group comprised physicians treating patients with AIDS therapy. Ease of administration of maintenance therapy and quality of patients' lives were considered important. BENEFITS, HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to i.v. maintenance therapy for patients with CMV retinitis. However, its low bio-availability precludes its use for induction therapy and necessitates careful monitoring for compliance. Compared with i.v. administration of ganciclovir, oral maintenance therapy is cost effective. EVIDENCE: Evidence for the guidelines was gathered from data presented at a symposium on CMV retinitis and oral ganciclovir, clinical trials of oral ganciclovir and input from a visiting expert. It was presented at a meeting of the advisory board whose members are involved in the care of patients with AIDS and the management of CMV retinitis. The guidelines were approved by each member of the advisory board. RECOMMENDATIONS: Diagnosis, treatment and follow-up of CMV retinitis should always be in consultation with an ophthalmologist who is experienced in treating this disease. The patient should be fully informed about the limitations of the oral form of ganciclovir; he or she should be involved in decision making and carefully monitored. Oral ganciclovir should not be used for induction therapy or for maintenance therapy in high-risk patients. VALIDATION: Similar guidelines have been produced in England where the drug has been available since January 1995. SPONSOR: The deliberations of the advisory board and the preparation of this report were funded through an educational grant from Hoffmann-La Roche (Canada).