Page 174 - Fluorescence-guided cancer surgery

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Chapter 10
procedure. Our assessment of TBR at all doses revealed that the TBR of uorescent lesions was maintained throughout the surgical procedure (i.e., 2-6 hours after dosing). However, because the uorescent lesions were resected during surgery, we were unable to track the TBR of individual lesions over time.
A su ciently high TBR is needed in order to optimally detect the tumor; in our study, a TBR of approximately 4.4 allowed the clear detection of tumor deposits. Higher doses (non-quenched) of OTL38 may translate into higher TBR, assuming linear binding of the agent to the tumor and background tissue. However, because the tumor contains a xed number of receptors, it is conceivable that even with a low dose, the majority of FRα molecules in the tumor tissue will be bound by the agent. Therefore, higher doses will not necessarily increase the tumor-speci c signal but might lead to increased nonsaturable, nonspeci c background binding, resulting in a less favorable TBR at higher doses. Indeed, the highest dose used in this study (0.05 mg/kg) resulted in a high background signal and lower TBR value, whereas the lowest dose tested (0.0125 mg/kg) yielded the highest TBR and—most importantly— the mildest symptoms. To obtain the best imaging results, the exposure times di ered between the di erent dosing groups; thus, the lowest dose (0.0125 mg/kg) required the longest exposure time (75 ms). Nevertheless, even this relatively longer exposure time enabled us to perform real-time imaging.
When translated to our patient cohort, the optimal dose of OTL38 (i.e., 0.0125 mg/kg) enabled the surgeons to successful identify malignant lesions with reasonably high sensitivity and speci city. Moreover, 29% of all resected malignant lesions would have gone undetected without the aid of uorescence- based imaging. Unfortunately, the relatively low number of patients precluded our ability to calculate the speci city and sensitivity of the technique. Moreover, our inability to study true negatives precluded a clear assessment of speci city. Nevertheless, both the in situ and ex vivo visual detection of lesions were clearly improved by the use of uorescence-based imaging. With respect to in situ detection, 29% more lesions were resected. However, even this increase may underestimate the total number of lesions that could be detected during surgery, as resection is dependent upon several factors other than detection. Lastly, our ex vivo visual detection was performed using still images, as it was not feasible to count lesions during surgery. Although this approach is commonly used and yields useful information, it may be considered suboptimal, as three- dimensional and tactile information is lost.