First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma.

PURPOSE: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery. EXPERIMENTAL DESIGN: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer. RESULTS: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio. CONCLUSIONS: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.

Development of a national medical leadership competency framework: the Dutch approach.

BACKGROUND: The concept of medical leadership (ML) can enhance physicians' inclusion in efforts for higher quality healthcare. Despite ML's spiking popularity, only a few countries have built a national taxonomy to facilitate ML competency education and training. In this paper we discuss the development of the Dutch ML competency framework with two objectives: to account for the framework's making and to complement to known approaches of developing such frameworks. METHODS: We designed a research approach and analyzed data from multiple sources based on Grounded Theory. Facilitated by the Royal Dutch Medical Association, a group of 14 volunteer researchers met over a period of 2.5 years to perform: 1) literature review; 2) individual interviews; 3) focus groups; 4) online surveys; 5) international framework comparison; and 6) comprehensive data synthesis. RESULTS: The developmental processes that led to the framework provided a taxonomic depiction of ML in Dutch perspective. It can be seen as a canonical 'knowledge artefact' created by a community of practice and comprises of a contemporary definition of ML and 12 domains, each entailing four distinct ML competencies. CONCLUSIONS: This paper demonstrates how a new language for ML can be created in a healthcare system. The success of our approach to capture insights, expectations and demands relating leadership by Dutch physicians depended on close involvement of the Dutch national medical associations and a nationally active community of practice; voluntary work of diverse researchers and medical practitioners and an appropriate research design that used multiple methods and strategies to circumvent reverberation of established opinions and conventionalisms. IMPLICATIONS: The experiences reported here may provide inspiration and guidance for those anticipating similar work in other countries to develop a tailored approach to create a ML framework.