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Purpose: Current methods of assessing disease burden in gastric adenocarcinoma are imperfect. Improved visualization during surgery with intraoperative molecular imaging (IMI) could improve gastric adenocarcinoma staging and guide surgical decision-making. The goal of this study was to evaluate if IMI with a folate receptor-targeted near-infrared fluorescent agent, OTL38, could identify gastric adenocarcinomas during surgery., Procedures: Five patients were enrolled in an IMI clinical trial. Patients received a folate receptor-targeted near-infrared dye (OTL38) 1.5-6 h prior to surgery. During staging laparoscopy and gastric resection, IMI was utilized to identify the primary tumor and any fluorescent lymph nodes. Resected tumors were analyzed for folate receptor alpha (FRα) and CD68 expression using immunohistochemistry. Microscopic OTL38 accumulation was examined with immunofluorescence., Results: Four out of five patients underwent total or subtotal gastrectomy; one had a staging laparoscopy only. All four patients who underwent gastric resection had invasive gastric adenocarcinoma; three had fluorescent tumors, mean tumor to background ratio (TBR) 4.1 ± 2.9. The one patient with a non-fluorescent tumor had a T1a tumor with two 0.4 cm tumor foci within a larger polyp. In each case with a fluorescent tumor, the fluorescence was evident from the exterior of the stomach. Two of the fluorescent tumors had modest FRα expression and no CD68 expression. One fluorescent tumor had high CD68 expression and no FRα expression., Conclusions: Intraoperative molecular imaging of gastric adenocarcinoma with OTL38 is feasible. Further studies should evaluate the clinical utility of this technique.

Objective: To determine if intraoperative near-infrared (NIR) imaging carries benefit in resection of pancreatic neoplasms., Background: Resection of pancreatic malignancies is hindered by high rates of local and distant recurrence from positive margins and unrecognized metastases. Improved tumor visualization could improve outcomes. We hypothesized that intraoperative NIR imaging with a clinically approved optical contrast agent could serve as a useful adjunct in assessing margins and extent of disease during pancreatic resections., Methods: Twenty patients were enrolled in an open-label clinical trial from July 2016 to May 2018. Subjects received second window indocyanine green (ICG) (2.5-5 mg/kg) 24 hours prior to pancreatic resection. NIR imaging was performed during staging laparoscopy and after pancreas mobilization in situ and following resection ex vivo. Tumor fluorescence was quantified using tumor-to-background ratio (TBR). Fluorescence at the specimen margin was compared to pathology evaluation., Results: Procedures included 9 pancreaticoduodenectomies, 10 distal pancreatectomies, and 1 total pancreatectomy; 21 total specimens were obtained. Three out of 8 noninvasive tumors were fluorescent (mean TBR 2.59 ± 2.57). Twelve out of 13 invasive malignancies (n = 12 pancreatic adenocarcinoma, n = 1 cholangiocarcinoma) were fluorescent (mean TBR 4.42 ± 2.91). Fluorescence at the transection margin correlated with final pathologic assessment in 12 of 13 patients. Following neoadjuvant therapy, 4 of 5 tumors were fluorescent; these 4 tumors showed no treatment response on pathology assessment. One tumor had a significant treatment response and showed no fluorescence., Conclusions: Second window ICG reliably accumulates in invasive pancreatic malignancies and provides real-time feedback during pancreatectomy. NIR imaging may help to assess the response to neoadjuvant therapy.

Purpose: Intraoperative localization and resection of ill-defined pulmonary ground-glass opacities (GGOs) during minimally invasive pulmonary resection is technically challenging. Current preoperative techniques to facilitate localization of GGOs include microcoil and hook wire placement, both of which have logistic limitations, carry safety concerns, and do not help with margin assessment. In this clinical trial, we explored an alternative method involving near-infrared molecular imaging with a folate receptor-targeted agent, OTL38, to improve localization of GGOs and confirmation of resection margins., Methods: In a human trial, 20 subjects with pulmonary GGOs who were eligible for video-assisted thoracoscopic surgery (VATS) resection received 0.025 mg/kg of OTL38 before the resection. The primary objectives were to (1) determine whether use of OTL38 allows safe localization of GGOs and assessment of margins during VATS and (2) determine patient, radiographic, and histopathologic variables that predict the amount of fluorescence during near-infrared imaging., Results: We observed no toxicity. Of the 21 GGOs, 20 accumulated OTL38 and displayed fluorescence upon in situ or back table evaluation. Intraoperatively, near-infrared imaging localized 15 of 21 lesions whereas VATS alone localized 10 of 21 (p = 0.05). The addition of molecular imaging affected care of nine of 21 subjects by improving intraoperative localization (n = 6) and identifying close margins (n = 3). This approach was most effective for subpleural lesions measuring less than 2 cm. For lesions deeper than 1.5 cm from the pleural surface, intraoperative localization using fluorescent feedback was limited., Conclusions: This approach provides a safe alternative for intraoperative localization of small, peripherally located pulmonary lesions. In contrast to alternative localization techniques, use of OTL38 also allows confirmation of adequate margins. Future studies will compare this approach to alternative localization techniques in a clinical trial., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Non-small cell lung cancer (NSCLC) is the number one cancer killer in the United States. Despite attempted curative surgical resection, nearly 40% of patients succumb to recurrent disease. High recurrence rates may be partially explained by data suggesting that 20% of NSCLC patients harbor synchronous disease that is missed during resection. In this report, we describe the use of a novel folate receptor-targeted near-infrared contrast agent (OTL38) to improve the intraoperative localization of NSCLC during pulmonary resection. Using optical phantoms, fluorescent imaging with OTL38 was associated with less autofluorescence and greater depth of detection compared to traditional optical contrast agents. Next, in in vitro and in vivo NSCLC models, OTL38 reliably localized NSCLC models in a folate receptor-dependent manner. Before testing intraoperative molecular imaging with OTL38 in humans, folate receptor-alpha expression was confirmed to be present in 86% of pulmonary adenocarcinomas upon histopathologic review of 100 human pulmonary resection specimens. Lastly, in a human feasibility study, intraoperative molecular imaging with OTL38 accurately identified 100% of pulmonary adenocarcinomas and allowed for identification of additional subcentimeter neoplastic processes in 30% of subjects. This technology may enhance the surgeon's ability to identify NSCLC during oncologic resection and potentially improve long-term outcomes., (Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Background: In early-stage esophageal adenocarcinoma (EAC), esophagectomy improves staging but also increases mortality compared with endoscopic resection. Our objective was to quantify esophagectomy mortality and lymph node metastasis (LNM) risk in early-stage EAC to improve surgical treatment allocation., Methods: We identified National Cancer Database (2004-2014) patients with nonmetastatic, Tis, T1a, or T1b EAC who had primary surgical resection and microscopic examination of at least 15 lymph nodes. Univariate and multivariable logistic regression identified predictors of LNM. Cox regression identified predictors of death. The Kaplan-Meier method predicted overall survival (OS)., Results: In 782 patients, LNM rates were: all patients 13.8%, Tis 0%, T1a 3.6%, T1b 23.4%. Independent predictors of LNM were submucosal invasion, lymphovascular invasion (LVI), decreasing differentiation, and tumor size ≥ 2 cm (P < 0.05). For T1a tumors with poor differentiation or size ≥ 2 cm, LNM rates were 10.2 and 6.7%, respectively; 90-day mortality was 3.1%. The LNM rate in well differentiated T1b tumors < 2 cm was 4.2%; 90-day mortality was 6.0%. Estimated 5-year OS was 80.2% versus 64.4% (T1a vs. T1b). LNM increased risk of death for T1a (hazard ratio [HR] 8.52, 95% confidence interval [CI] 3.13-23.22, P < 0.001) and T1b tumors (HR 2.52, 95% CI 1.59-4.00, P < 0.001)., Conclusions: In T1a EAC with poor differentiation or size ≥ 2 cm, esophagectomy should be considered, whereas in T1b EAC with low-risk features (well-differentiated T1b EAC < 2 cm without LVI), endoscopic resection may be sufficient. Treatment guidelines for early-stage EAC should include all high-risk tumor features for LNM and stage-specific esophagectomy mortality.

Background: During minimally invasive pulmonary resection, both limited visualization and tactile feedback can make localization of pulmonary nodules and assessment for synchronous disease challenging. Intraoperative molecular imaging is an emerging technology that can enhance a surgeon's ability to detect cancers at the time of resection., Case Presentation: In this report, we describe the application of a folate receptor-targeted, near infrared optical contrast agent (OTL38) for the detection of an invasive pulmonary adenocarcinoma. During molecular imaging, an otherwise undetectable synchronous nodule was also identified. This finding resulted in intraoperative upstaging and operative plan modifications., Conclusion: This report marks the first successful utilization of a targeted, near infrared intraoperative molecular imaging probe useful for thoracic malignancies. This rapidly evolving technology may enhance the surgeon's ability to perform a number of oncologic procedures including tumor localization, margin assessment and intraoperative staging.

Objective: To determine if intraoperative molecular imaging (IMI) can improve detection of malignant pulmonary nodules., Background: 18-Fluorodeoxyglucose positron emission tomography (PET) is commonly utilized in preoperative assessment of patients with solid malignancies; however, false negatives and false positives remain major limitations. Using patients with pulmonary nodules as a study model, we hypothesized that IMI with a folate receptor targeted near-infrared contrast agent (OTL38) can improve malignant pulmonary nodule identification when combined with PET., Methods: Fifty patients with pulmonary nodules with imaging features suspicious for malignancy underwent preoperative PET. Patients then received OTL38 before pulmonary resection. During resection, IMI was utilized to evaluate known pulmonary nodules and identify synchronous lesions. Tumor size, PET standardized uptake value, and IMI tumor-to-background ratios were compared for known and synchronous nodules via paired and unpaired t tests, when appropriate. Test characteristics of PET and IMI with OTL38 were compared., Results: IMI identified 56 of 59 (94.9%) malignant pulmonary nodules identified by preoperative imaging. IMI located an additional 9 malignant lesions not identified preoperatively. Nodules only detected by IMI were smaller than nodules detected preoperatively (0.5 vs 2.4 cm; P < 0.01), but displayed similar fluorescence (tumor-to-background ratio 3.3 and 3.1; P = 0.50). Sensitivity of IMI and PET were 95.6% and 73.5% (P = 0.001), respectively; and positive predictive values were 94.2% and 89.3%, respectively (P > 0.05). Additionally, utilization of IMI clinically upstaged 6 (12%) subjects and improved management of 15 (30%) subjects., Conclusions: These data suggest that combining IMI with PET may provide superior oncologic outcomes for patients with resectable lung cancer.

Background: Patients with locally advanced rectal cancer typically receive neoadjuvant chemoradiation followed by total mesorectal excision. Other treatment approaches, including transanal techniques and close surveillance, are becoming increasingly common following positive responses to chemoradiation. Lack of pathologic lymph node staging is one major disadvantage of these novel strategies., Objective: The purposes of this study were to determine clinicopathologic factors associated with positive lymph nodes following neoadjuvant chemoradiation for rectal cancer and to create a nomogram using these factors to predict rates of lymph node positivity., Design: This is a retrospective cohort analysis., Settings: This study used the National Cancer Database., Patients: Patients aged 18 to 90 with clinical stage T3/T4, N0, M0 or Tany, N1-2, M0 adenocarcinoma of the rectum who underwent neoadjuvant chemoradiation before total mesorectal excision from 2010 to 2012 were identified., Main Outcome Measures: The primary outcome measure was lymph node positivity after neoadjuvant chemoradiation for locally advanced rectal cancer. Bivariate and multivariate analyses were used to determine the associations of clinicopathologic variables with lymph node positivity., Results: Eight thousand nine hundred eighty-four patients were included. Young age, lower Charlson score, mucinous histology, poorly differentiated and undifferentiated tumors, the presence of lymphovascular invasion, elevated CEA level, and clinical lymph node positivity were significantly predictive of pathologic lymph node positivity following neoadjuvant chemoradiation. The predictive accuracy of the nomogram is 70.9%, with a c index of 0.71. There was minimal deviation between the predicted and observed outcomes., Limitations: This study is retrospective, and it cannot be determined when in the course of treatment the data were collected., Conclusions: We created a nomogram to predict lymph node positivity following neoadjuvant chemoradiation for locally advanced rectal cancer that can serve as a valuable complement to imaging to aid clinicians and patients in determining the best treatment strategy.

Purpose: Intraoperative molecular imaging (IMI) is an emerging technology used to locate pulmonary adenocarcinomas and identify positive margins during surgery. Background noise and tissue autofluorescence have been major obstacles. The goal of this study is to optimize the image quality of folate receptor alpha (FRα) targeted IMI for pulmonary adenocarcinomas by modifying emission data.Procedures: A total of 15 lung cancer patients were enrolled in a pilot study. In the first cohort, FRα upregulation within pulmonary adenocarcinoma tumors was confirmed by analyzing specimens from five pulmonary adenocarcinoma patients with flow cytometry and immunohistochemistry. Next, in a cohort of five additional patients, autofluorescence of intrathoracic structures and tissues was quantified. Lastly, five patients with tumors at various depths from the pleural surface were enrolled and received the FRα-targeted optical contrast agent, EC17. In this final cohort, resected pulmonary adenocarcinomas were imaged at a wide range of fluorescence exposure times (0 to 200 ms), various laser powers, and with unique filter configurations. Tumor-to-noise ratio (TNR) for images was generated using region of interest software.Results: Pulmonary adenocarcinomas highly express FRα. Significant autofluorescence from native thoracic tissues was found with the highest fluorescent signals at the bronchial stump (547 ± 98, range 423-699), the pulmonary artery (267 ± 64, range 200-374), and cortical bone (266 ± 17, range 243-287). High levels of autofluorescence were appreciated after systemic administration of EC17; however, TNR was improved by altering exposure settings at the time of the imaging. Optimal fluorescent exposure time occurs at 40 ms (25 frames/s).Conclusions: Exposure properties can be manipulated to maximize TNR thus allowing for successful intraoperative detection of pulmonary adenocarcinomas during surgery. Optimization of the conditions for intraoperative molecular imaging sets the stage for future clinical trials utilizing targeted IMI techniques which can aid the surgeon at the time of cancer resection. [ABSTRACT FROM AUTHOR]