Intraoperative fluorescence imaging in thoracic surgery Newton, Andrew D.; Predina, Jarrod D.; Nie, Shuming ...
Journal of surgical oncology,
August 1, 2018, 2018-Aug, 2018-08-00, 20180801, Volume:
118, Issue:
2
Journal Article
Peer reviewed
Open access
Intraoperative fluorescence imaging (IFI) can improve real‐time identification of cancer cells during an operation. Phase I clinical trials in thoracic surgery have demonstrated that IFI with second ...window indocyanine green (TumorGlow®) can identify subcentimeter pulmonary nodules, anterior mediastinal masses, and mesothelioma, while the use of a folate receptor‐targeted near‐infrared agent, OTL38, can improve the specificity for diagnosing tumors with folate receptor expression. Here, we review the existing preclinical and clinical data on IFI in thoracic surgery.
To determine if intraoperative near-infrared (NIR) imaging carries benefit in resection of pancreatic neoplasms.
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.
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.
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.
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.
Intraoperative identification of pulmonary nodules, particularly small lesions, can be challenging. We hypothesize that folate receptor-targeted intraoperative molecular imagining can be safe and ...improve localization of pulmonary nodules during resection.
Twenty subjects with biopsy-proven pulmonary adenocarcinomas were enrolled in a phase I clinical trial to test the safety and feasibility of OTL38, a novel folate receptor-α (FRα) targeted optical contrast agent. During resection, tumors were imaged in situ and ex vivo and fluorescence was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemistry was utilized to quantify FRα expression. A multivariate analysis using clinical and tumor data was performed to determine variables impacting tumor fluorescence.
Of the 20 subjects, three grade I adverse events were observed: all transient nausea/abdominal pain. All symptoms resolved after completing the infusion. Sixteen of 20 subjects (80%) had tumors with in situ fluorescence with a mean tumor-to-background fluorescence level of 2.9 (interquartile range, 2.1 to 4.2). The remaining 4 subjects' tumors fluoresced ex vivo. In situ fluorescence was dependent on depth from the pleural surface. Four subcentimeter nodules not identified on preoperative imaging were detected with intraoperative imaging.
This phase I trial provides preliminary evidence suggesting that folate receptor-targeted molecular imaging with OTL38 is safe, with tolerable grade I toxicity. These data also suggest that OTL38 accumulates in known lung cancers and may improve identification of synchronous malignancies. Our group is initiating a five-center, phase II study to better understand the clinical implications of intraoperative molecular imaging using OTL38.
Prolonged radiation treatment (RT) time (RTT) has been associated with worse survival in several malignancies. The present study investigated whether delays during RT are associated with overall ...survival (OS) in non-small cell lung cancer (NSCLC).
The National Cancer Database was queried for patients with stage III NSCLC who had received definitive concurrent chemotherapy and fractionated RT to standard doses (59.4-70.0 Gy) and fractionation from 2004 to 2013. The RTT was classified as standard or prolonged for each treatment regimen according to the radiation dose and number of fractions. Cox proportional hazards models were used to evaluate the association between the following factors and OS: RTT, RT fractionation, demographic and pathologic factors, and chemotherapeutic agents.
Of 14,154 patients, the RTT was prolonged in 6262 (44.2%). Factors associated with prolonged RTT included female sex (odds ratio OR 1.21, P<.0001), black race (OR 1.20, P=.001), nonprivate health insurance (OR 1.30, P<.0001), and lower income (<$63,000 annually, OR 1.20, P<.0001). The median OS was significantly worse for patients with prolonged RTT than that for those with standard RTT (18.6 vs 22.7 months, P<.0001). Furthermore, the OS worsened with each cumulative interval of delay (standard RTT vs prolonged 1-2 days, 20.5 months, P=.009; prolonged 3-5 days, 17.9 months, P<.0001; prolonged 6-9 days, 17.7 months, P<.0001; prolonged >9 days, 17.1 months, P<.0001). On multivariable analysis, prolonged RTT was independently associated with inferior OS (hazard ratio 1.21, P<.0001). Prolonged RTT as a continuous variable was also significantly associated with worse OS (hazard ratio 1.001, P=.0007).
Delays during RT appear to negatively affect survival for patients with locally advanced NSCLC. We have detailed the demographic and socioeconomic barriers influencing prolonged RTT as a method to address the health disparities in this regard. Cumulative interruptions of RT should be minimized.
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.
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Predina et al. explore folate receptor-targeted intraoperative molecular imaging in preclinical models and humans with non-small cell lung cancer.
Near-infrared (NIR) imaging using the second time window of indocyanine green (ICG) allows localization of pulmonary, pleural, and mediastinal malignancies during surgery. Based on empirical ...evidence, we hypothesized that different histologic tumor types fluoresce optimally at different ICG doses.
Patients with thoracic tumors biopsy-proven or suspicious for malignancy were enrolled in an NIR imaging clinical trial. Patients received a range of ICG doses 1 day before surgery: 1 mg/kg (n = 8), 2 mg/kg (n = 8), 3 mg/kg (n = 13), 4 mg/kg (n = 8), and 5 mg/kg (n = 8). Intraoperatively, NIR imaging was performed. The endpoint was to identify the highest tumor-to-background fluorescence ratio (TBR) for each tumor type at each dose. Final pathology confirmed tumor histology.
Of 45 patients, 41 had malignancies (18 non-small cell lung cancers NSCLC, 3 pulmonary neuroendocrine tumors, 13 thoracic metastases, 4 thymomas, 3 mesotheliomas). At doses of 4 to 5 mg/kg, the TBR from primary NSCLC vs other malignancies was no different (2.70 vs 3.21, p = 1.00). At doses of 1 to 3 mg/kg, the TBR was greater for the NSCLCs (3.19 vs 1.49, p = 0.0006). Background fluorescence from the heart or ribs was observed in 1 of 16 cases at 1 to 2 mg/kg, 5 of 13 cases at 3 mg/kg, and 14 of 16 cases at 4 to 5 mg/kg; this was a major determinant of dose optimization.
This is the first study to demonstrate that the optimal NIR contrast agent dose varies by tumor histology. Lower dose ICG (2 to 3 mg/kg) is superior for nonprimary lung cancers, and high dose ICG (4 to 5 mg/kg) is superior for lung cancers. This will have major implications as more intraoperative imaging trials surface in other specialties, will significantly reduce costs and may facilitate wider application.
Intraoperative molecular imaging (IMI) may improve surgical outcomes during pulmonary resection for lung cancer. A multiinstitutional phase 2 IMI clinical trial was conducted using a near-infrared, ...folate receptor-targeted contrast agent for lung adenocarcinomas, OTL38. The primary goal was to determine whether OTL38 improved surgeons' ability to identify difficult to find nodules, occult cancers, and positive margins.
Patients with lung nodules received OTL38 (0.025 mg/kg) preoperatively. Patients had IMI sequentially during lung inspection, tumor resection, and margin check. Efficacy was evaluated by occurrence of clinically significant events, occurrences that caused the surgeon to modify the operation or upstage the patient's cancer. Safety was assessed for a single intravenous dose of OTL38.
Of 110 patients recruited, 92 were eligible for analysis. During lung inspection, IMI found 24 additional nodules, 9 (10%) of which were cancers that had not been known preoperatively. During tumor resection, IMI located 11 (12%) lesions that the surgeon could not find. During the margin check, IMI revealed 8 positive margins (9%) that the surgeon thought were negative. Benefits of IMI were pronounced in patients undergoing sublobar pulmonary resections and in patients with ground-glass opacities. There were no serious adverse events. All surgeons felt comfortable with the procedures by 10 cases.
In this phase 2 clinical trial, IMI improved outcomes for 26% of patients. A randomized, multiinstitutional phase 3 clinical trial is underway.
Background
The management of most solid tumors of the anterior mediastinum involves complete resection. Because of their location near mediastinal structures, wide resection is not possible; ...therefore, surgeons must use subjective visual and tactile cues to determine disease extent. This clinical trial explored intraoperative near‐infrared (NIR) imaging as an approach to improving tumor delineation during mediastinal tumor resection.
Methods
Twenty‐five subjects with anterior mediastinal lesions suspicious for malignancy were enrolled in an open‐label feasibility trial. Subjects were administered indocyanine green (ICG) at a dose of 5 mg/kg, 24 hours before resection (via a technique called TumorGlow). The NIR imaging systems included Artemis (Quest, Middenmeer, the Netherlands) and Iridium (VisionSense Corp, Philadelphia, Pennsylvania). Intratumoral ICG uptake was evaluated. The clinical value was determined via an assessment of the ability of NIR imaging to detect phrenic nerve involvement or incomplete resection. Clinical and histopathologic variables were analyzed to determine predictors of tumor fluorescence.
Results
No drug‐related toxicity was observed. Optical imaging added a mean of 10 minutes to case duration. Among the subjects with solid tumors, 19 of 20 accumulated ICG. Fluorescent tumors included thymomas (n = 13), thymic carcinomas (n = 4), and liposarcomas (n = 2). NIR feedback improved phrenic nerve dissection (n = 4) and identified residual disease (n = 2). There were no false‐positives or false‐negatives. ICG preferentially accumulated in solid tumors; this was independent of clinical and pathologic variables.
Conclusions
NIR imaging for anterior mediastinal neoplasms is safe and feasible. This technology may provide a real‐time tool capable of determining tumor extent and specifically identify phrenic nerve involvement and residual disease.
During the resection of anterior mediastinal masses, the intraoperative identification of phrenic nerve involvement and positive margins may be challenging. Near‐infrared imaging may provide a real‐time tool capable of determining tumor extent and may specifically identify phrenic nerve involvement and residual disease.
Pulmonary metastasectomy for osteosarcoma provides a select group of patients an opportunity for long-term survival and possible cure. Unfortunately, a complete metastasectomy is challenging due an ...inability to accurately identify lesions that lay below the threshold of preoperative imaging or intraoperative visual and tactile inspection. Growing evidence suggests that osteosarcomas express a number of unique molecular markers, including the folate receptor alpha. In this case report, we describe the application of a folate receptor-targeted, near-infrared optical contrast agent (OTL38) to improve osteosarcoma localization during minimally invasive pulmonary resection. In addition to localizing preoperatively identified lesions, this technology helped identify additional disease that was undetected on preoperative imaging or with traditional intraoperative techniques. This report marks the first successful utilization of a molecular imaging probe useful for osteosarcomas. This technology may provide a unique approach to improve pulmonary metastasectomy of osteosarcomas.
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