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Original Investigation
August 25, 2021

Targeted Intraoperative Molecular Imaging for Localizing Nonpalpable Tumors and Quantifying Resection Margin Distances

Author Affiliations
  • 1Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 2Department of Chemistry, Purdue University, West Lafayette, Indiana
JAMA Surg. Published online August 25, 2021. doi:10.1001/jamasurg.2021.3757
Key Points

Question  Can intraoperative molecular imaging localize nonpalpable, visually occult tumors and accurately predict margin adequacy during resection?

Findings  In this nonrandomized open-label trial of 40 adults with a T1 pulmonary lesion radiographically suspicious for a nonpalpable cancer, 83% of nonpalpable, nonvisible lesions were identified by intraoperative molecular imaging and intraoperative molecular imaging–calculated margins were nearly identical to those reported on final pathology.

Meaning  By identifying occult tumors and cancer-positive margins that may have been missed by conventional surgical methods, intraoperative molecular imaging can improve surgical management of nonpalpable tumors across the field of surgical oncology.


Importance  Complete (R0) resection is the dominant prognostic factor for survival across solid tumor types. Achieving adequate tumor clearance with appropriate margins is particularly difficult in nonpalpable tumors or in situ disease. Previous methods to address this problem have proven time consumptive, impractical, or ineffective.

Objective  To assess the capability of intraoperative molecular imaging (IMI), a novel technology using a fluorescent tracer targeted to malignant cells, to localize visually occult, nonpalpable tumors and quantify margin distances during resection.

Design, Setting, and Participants  This nonrandomized open-label trial of IMI using a folate receptor-targeted fluorescent tracer enrolled patients between May 2017 and June 2020 at a single referral center. Eligible patients included those with a small (T1) lung lesion suspicious for malignant neoplasms and with radiographic features suggestive of a nonpalpable lesion.

Interventions  Patients were preoperatively infused with a folate receptor-targeted near-infrared tracer. Intraoperatively, surgeons used thoracoscopic visualization and palpation to identify lesions. IMI was performed to detect the lesion in situ, and lesions were imaged ex vivo. Margins were assessed by IMI before comparison with those reported on final histopathologic analysis.

Main Outcomes and Measures  The main outcomes were whether IMI could (1) localize nonpalpable lung lesions in situ and (2) quantify margin distance with comparison with final pathology as the criterion standard. Patient demographic information and lesion characteristics were prospectively recorded.

Results  Of 40 patients, 26 (65%) were female, and the median (interquartile range) age was 66.5 (62-72) years. Conventional surgical methods localized 22 of 40 lesions (55%), while IMI localized 36 of 40 (90%). Of 18 nonpalpable lesions, 15 (83.3%) were identified by IMI. Both palpable and nonpalpable lesions demonstrated mean signal-to-background ratio more than 2. An IMI margin was able to be calculated for 39 of 40 patients (95%). IMI margins were nearly identical to margins reported on final pathology (R2 = 0.9593), with median (interquartile range) difference of 1.3 (0.7-2.0) mm. IMI detected 2 margins in nonpalpable tumors that were clinically unacceptable and would have had a high probability of recurrence.

Conclusions and Relevance  To our knowledge, this study presents the first clinical use of IMI for nonpalpable tumors and provides proof of principle for the utility of IMI across the field of surgical oncology in identifying occult disease and tumor-positive margins.

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