Pudexacianinium (ASP5354) chloride for ureter visualization in participants undergoing laparoscopic, minimally invasive colorectal surgery.

BACKGROUND: Intraoperative ureteral injury, a serious complication of abdominopelvic surgeries, can be avoided through ureter visualization. Near-infrared fluorescence imaging offers real-time anatomical visualization of ureters during surgery. Pudexacianinium (ASP5354) chloride is an indocyanine green derivative under investigation for intraoperative ureter visualization during colorectal or gynecologic surgery in adult and pediatric patients. METHODS: In this phase 2 study (NCT04238481), adults undergoing laparoscopic colorectal surgery were randomized to receive one intravenous dose of pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg. The primary endpoint was successful intraoperative ureter visualization, defined as observation of ureter fluorescence 30 min after pudexacianinium administration and at end of surgery. Safety and pharmacokinetics were also assessed. RESULTS: Participants received pudexacianinium 0.3 mg (n = 3), 1.0 mg (n = 6), or 3.0 mg (n = 3). Most participants were female (n = 10; 83.3%); median age was 54 years (range 24-69) and median BMI was 29.3 kg/m2 (range 18.7-38.1). Successful intraoperative ureter visualization occurred in 2/3, 5/6, and 3/3 participants who received pudexacianinium 0.3 mg, 1.0 mg, or 3.0 mg, respectively. Median intensity values per surgeon assessment were 1 (mild) with the 0.3-mg dose, 2 (moderate) with the 1.0-mg dose, and 3 (strong) with the 3.0-mg dose. A correlation was observed between qualitative (surgeon's recognition/identification of the ureter during surgery) and quantitative (video recordings of the surgeries after study completion) assessment of fluorescence intensity. Two participants experienced serious adverse events, none of which were drug-related toxicities. One adverse event (grade 1 proteinuria) was related to pudexacianinium. Plasma pudexacianinium concentrations were dose-dependent and the mean (± SD) percent excreted into urine during surgery was 22.3% ± 8.0% (0.3-mg dose), 15.6% ± 10.0% (1.0-mg dose), and 39.5% ± 12.4% (3.0-mg dose). CONCLUSIONS: In this study, 1.0 and 3.0 mg pudexacianinium provided ureteral visualization for the duration of minimally invasive, laparoscopic colorectal procedures and was safe and well tolerated.

Regulatory Aspects of Optical Methods and Exogenous Targets for Cancer Detection.

Considerable advances in cancer-specific optical imaging have improved the precision of tumor resection. In comparison to traditional imaging modalities, this technology is unique in its ability to provide real-time feedback to the operating surgeon. Given the significant clinical implications of optical imaging, there is an urgent need to standardize surgical navigation tools and contrast agents to facilitate swift regulatory approval. Because fluorescence-enhanced surgery requires a combination of both device and drug, each may be developed in conjunction, or separately, which are important considerations in the approval process. This report is the result of a one-day meeting held on May 4, 2016 with officials from the National Cancer Institute, the FDA, members of the American Society of Image-Guided Surgery, and members of the World Molecular Imaging Society, which discussed consensus methods for FDA-directed human testing and approval of investigational optical imaging devices as well as contrast agents for surgical applications. The goal of this workshop was to discuss FDA approval requirements and the expectations for approval of these novel drugs and devices, packaged separately or in combination, within the context of optical surgical navigation. In addition, the workshop acted to provide clarity to the research community on data collection and trial design. Reported here are the specific discussion items and recommendations from this critical and timely meeting. Cancer Res; 77(9); 2197-206. ©2017 AACR.

Diffuse reflectance spectroscopy in Barrett's esophagus: developing a large field-of-view screening method discriminating dysplasia from metaplasia.

We evaluated diffuse reflectance spectroscopy implemented as a small field-of-view technique for discrimination of dysplasia from metaplasia in Barrett's esophagus as an adjuvant to autofluorescence endoscopy. Using linear discriminant analysis on 2579 spectra measured in 54 patients identified an optimum a 4-wavelength classifier (at 485, 513, 598 and 629 nm). Sensitivity and specificity for a test data set were 0.67 and 0.85, respectively. Spectroscopic results show that this technique could be implemented in wide-field imaging mode to improve the accuracy of existing endoscopy techniques for finding early pre-malignant lesions in Barrett's esophagus. Results show that the discrimination occurs likely due to redistribution of blood content in the tissue sensed by the optical probing with the wavelength-dependent sampling depth.

Assessment of photobleaching during endoscopic autofluorescence imaging of the lower GI tract.

BACKGROUND AND OBJECTIVES: In autofluorescence endoscopy, the difference in the fluorescence of intrinsic fluorophores is imaged to help visualize pre-malignant lesions, as in the system evaluated here. In this, blue light is used for excitation and the green autofluorescence is normalized by the red diffuse reflectance and presented using a false color scale. The present study was designed to quantify the degree of fluorescence photobleaching induced by the excitation light during use in the colon, since significant photobleaching could lead to false interpretation of the images, particularly false-positive lesions. STUDY DESIGN: Measurements were made ex vivo and in vivo, both using the endoscopic imaging system and a separate fiberoptic spectroscopy probe in externalized rat jejunum and in patients undergoing routine colonoscopy, using exposures typical of autofluorescence endoscopic examination. RESULTS: Photobleaching could be potentially caused at blue light exposure. However, at light intensities and exposure times that are typically used in clinical practice, the average photobleaching (% loss of peak fluorescence intensity) was <1% and <6% in the rat and human tissues, respectively. Nevertheless, the range was large: from -17% to +18% in rats and -33% to +43% in patients, where negative values denote an apparent increase in fluorescence. Both the large positive and negative deviations are believed in part to be due to a measurement artifact caused by uncontrollable tissue motility. SUMMARY AND CONCLUSIONS: It is concluded that, using exposures typically encountered in clinical practice, there is minimal photobleaching during fluorescence endoscopy at exposure such as are used in the Onco-LIFE and comparable systems. The small changes in fluorescence intensity and spectral shift that do occur are not likely to be detectable by eye, and so should not impact significantly on the diagnostic accuracy of the technique.