Fundamentals and Application of New Bioproduction Systems

Abstract

Objectives: Cytoreductive surgery is widely used for the treatment of peritoneal dissemination in clinical practice. However, it is difficult to detect and remove tumors that are located deeply in the peritoneal cavity and easily changing the position during an operation. We have found that a PET probe 64Cu-PCTA-anti-EGFR antibody (cetuximab) highly accumulates in intraperitoneal tumors by intraperitoneal administration. While, we have developed the world's first open-type PET system, called "OpenPET". In this system, the detectors were arranged to make open space sufficient enough for surgical procedures; in addition it can image and track objects with high-resolution PET in a real-time manner. Here, we examined a feasibility of an OpenPET-guided surgery with 64Cu-PCTA-cetuximab to detect and remove intraperitoneal tumors of unknown position. Methods: Human colon cancer HCT116 cells stably expressing red fluorescent protein (HCT116-RFP) were intraperitoneally seeded into mice (1x107 cells/50 mu l PBS + 50 mu l Matrigel). At 1 week after cell inoculation, 64Cu-PCTA-cetuximab (7.4 MBq/mouse) was administered intraperitoneally. At 24 h later, the OpenPET-guided surgery was performed with a small prototype of the OpenPET. The prototype had a spatial resolution of about 3 mm. For the OpenPET real-time imaging, one-pass list-mode DRAMA (dynamic row-action maximum-likelihood algorithm) on graphics processing unit was used for high-speed reconstruction, which enables updating cycle of image less than one second while accumulating list-mode data. The parameters of the OpenPET imaging were as follows: voxel size was 1.5 mm; sensitivity and random corrections were applied; absorption and scatter corrections were not applied. Results: The OpenPET-guided surgery clearly detected tumors located deeply in the peritoneal cavity. Measurement time to accumulate sufficient list-mode data to identify the tumors was about 10-30 s. We resected the tumors located deeply in the peritoneal cavity while monitoring them with the OpenPET real-time imaging. In contrast, these tumors could not be visually identified without OpenPET. Moreover, the fluorescence of these tumors was not detected, since the tumors were located behind the intestines. It is worth noting that we successfully detected and removed 3-mm size small tumors located deeply using this system. OpenPET was useful to confirm the presence or absence of residual tumors during an operation. Conclusion: We developed an OpenPET-guided surgery with 64Cu-PCTA-cetuximab to detect and remove intraperitoneal tumors which could be hardly identifiable by conventional modalities. This method could provide a novel strategy of cytoreductive surgery for the patients with peritoneal dissemination from gastrointestinal cancers.