ABSTRACT
PURPOSE: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model. METHODS: The LEM2/15 antibody and IgG isotype control were radiolabelled with 89Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [177Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [177Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours. RESULTS: At 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [89Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [89Zr]Zr-Df-LEM2/15 and [177Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [177Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [177Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [177Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4-5 %). CONCLUSIONS: The results showed that the 89Zr/177Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.
ABSTRACT
OBJECTIVE: Primary objective is to determine the rate of intubation with inappropriately sized endotracheal tubes (ETTs) in a pediatric intensive care unit (PICU) in El Salvador. Secondary objective is to determine effectiveness of a video-based curriculum to teach local providers on pediatric advanced airway management and surgical approach to patients requiring airway reconstruction. METHODS: Data for 296 intubated pediatric patients was collected over a six month period in a 16-bed PICU in El Salvador. Results of a learning behavior assessment survey completed by local healthcare workers informed a curriculum to complement on-site education during annual surgical airway mission trips. The video-based curriculum addressed proper sizing and use of cuffed endotracheal tubes, care of the intubated child and perioperative considerations of the surgical airway patient. Providers completed pre and post-curriculum quizzes to measure knowledge acquisition. RESULTS: Over 6-months, 281 patients were intubated. Sixty-three percent had improperly sized ETTs. Thirty-one percent had a failed or accidental extubation. All-cause mortality was 24%. One hundred and fifty-nine Salvadorian providers completed a learning behavior survey informing a video-based curriculum. Sixty-four providers completed the curriculum. Post-curriculum quiz scores increased by 18.7%. Surgeons, anesthesiologist, intensivists and speech pathologists demonstrated significant improvement (pâ¯<â¯0.05). CONCLUSION: Nearly two-thirds of intubated patients in a PICU in El Salvador have improperly sized ETTs and one-third require reintubation following planned or accidental extubation. The development of this first of its kind video-based curriculum for critical care and surgical training regarding how to properly care for the intubated child is coupled with the development of a longitudinal database to record pediatric airway related morbidity and mortality in the largest pediatric hospital in El Salvador. This model and system can be used to track the reduction in airway related morbidity and mortality directly related to a systems based intervention both in El Salvador and then elsewhere.
