Improving Surgery in Pediatric Oncology by Fluorescence- and 3D imaging

Abstract

Pediatric oncologic surgery can be improved by bringing novel imaging strategies from the scientific bench to the operation room. This thesis focusses on 3D imaging innovation in surgery for children with neuroblastoma and Wilm’s tumors. By combining the latest 3D visualization developments with implemented imaging modalities for Wilms’ tumors (chapter 2), reviewing the literature on complications of neuroblastoma surgery (chapter 3), and by exploring the possibilities for new scientific visualization techniques during surgery of neuroblastoma (chapter 4) and using the latest 3D in vitro modelling technology (chapter 5 and 6), the first results were used to generate a protocol for a phase I clinical trial (chapter 7) using a near-infra red fluorescence antibody during surgery in pediatric oncology.

State of the art preoperative imaging is of paramount importance in achieving good results during oncological surgery. This thesis explored the possibility to bring new imaging techniques to the surgical theatre. 3D visualizations such as augmented reality and 3D printing should be implemented in the preoperative planning of bilateral Wilms tumors in assisting nephron sparing surgery. Implementation of fluorescence guided surgery as a precision tool could establish tumor resection of neuroblastoma with greater confidence, a lower risk of surgical complications and unbiased evaluation of the extent of tumor removal, thereby guiding the post-surgery course of treatment. This would fulfill an unmet need in high-risk neuroblastoma that could benefit a wide range of patients. Moreover, the comprehensive preclinical evaluation pipeline, encompassing organoid technology and multiple imaging techniques, can be applied towards the development of other targeted probes for fluorescence guided surgery. In this thesis, accurate quantification of fluorescence of the investigated probes was described and thereby tumor-specific labeling functionality in vitro and preliminary predictive in vivo potential was shown. In addition, future research can focus on merging the techniques described in this thesis; using augmented reality to visualize realtime tumor-specific fluorescence intra-operatively. In an ideal situation, all 3D visualization modalities will be combined during surgery. When it will be possible to accurately derive 3D visualizations from conventional imaging, the visualizations can be related to the individual anatomy of the patient. Eventually, augmented reality could combine the personalized anatomy with a fluorescence overlay with NIR-imaging with cellular preciseness and the future will shine bright for surgery in pediatric oncology.

Overall, to improve surgical outcome and to decrease the complication rate in the surgery of pediatric oncology, two main points are to be considered:

1. Investments in new visualization techniques providing real time feedback on cancerous tissue should be made to more accurately remove tumor tissue and decrease surgical related morbidity. It is worth investing further in these visualization techniques and assessing their synergy, when combined.

2. Collaboration between clinicians and scientist is essential, as created in the Princess Máxima Center and the reason behind originating the research described in this thesis. The centralization of surgery and having a specialized surgical team operating all pediatric solid tumors, is key to combine the best possible care with optimal research strategies.