ABSTRACT
3D organoid model technologies have led to the development of innovative tools for cancer precision medicine. Yet, the gold standard culture system (Matrigel®) lacks the ability for extensive biophysical manipulation needed to model various cancer microenvironments and has inherent batch-to-batch variability. Tunable hydrogel matrices provide enhanced capability for drug testing in breast cancer (BCa), by better mimicking key physicochemical characteristics of this disease's extracellular matrix. Here, we encapsulated patient-derived breast cancer cells in bioprinted polyethylene glycol-derived hydrogels (PEG), functionalized with adhesion peptides (RGD, GFOGER and DYIGSR) and gelatin-derived hydrogels (gelatin methacryloyl; GelMA and thiolated-gelatin crosslinked with PEG-4MAL; GelSH). Within ranges of BCa stiffnesses (1−6 kPa), GelMA, GelSH and PEG-based hydrogels successfully supported the growth and organoid formation of HR+,−/HER2+,− primary cancer cells for at least 2−3 weeks, with superior organoid formation within the GelSH biomaterial (up to 268% growth after 15 days). BCa organoids responded to doxorubicin, EP31670 and paclitaxel treatments with increased IC50 concentrations on organoids compared to 2D cultures, and highest IC50 for organoids in GelSH. Cell viability after doxorubicin treatment (1 µM) remained >2-fold higher in the 3D gels compared to 2D and doxorubicin/paclitaxel (both 5 µM) were ~2.75−3-fold less potent in GelSH compared to PEG hydrogels. The data demonstrate the potential of hydrogel matrices as easy-to-use and effective preclinical tools for therapy assessment in patient-derived breast cancer organoids.
ABSTRACT
BACKGROUND: Surgical outcomes research is limited in areas of the world with the greatest unmet surgical need and likely greatest variation in outcomes. Measurement alone may improve outcomes-the so-called Hawthorne effect. The purpose of this multicenter cohort study was to identify factors that are both feasible to collect and are associated with a major adverse event following a targeted procedure in Cape Town, South Africa. METHODS: A collaborative of four acute care surgical units was formed to develop a data set with minimal data burden describing outcomes after an emergency exploratory laparotomy during a 3-mo period (February-April 2015). Controlling for patient, problem, provider, procedure and process predictors, multivariate models were built to identify risk factors for a major adverse event and higher resource use after surgery in our collaborative. RESULTS: The outcomes of 450 exploratory laparotomies from the four participating hospitals were audited, 319 (70.9%) were for non-trauma and 131 (29.1%) were for trauma. The major adverse event rate was 15.7% (95% CI 12.6-19.4). In the multivariate analysis, factors associated with the primary outcome included age, American Society of Anesthesia score of greater than 2, bowel resection, preoperative CT scan, and a nontherapeutic laparotomy. A major adverse event was associated with all three outcomes assessing increased resource utilization. CONCLUSIONS: This study supports the comparative outcome assessment of a high-volume or high-risk procedure as a proxy for measuring the quality of care provided in a surgical collaborative. Such an exercise can identify opportunities for quality improvement.
