Lung cancer screening has lead to frequent diagnosis of solitary pulmonary nodules (SPNs), many of which require surgical biopsy for diagnosis and intervention. Subcentimeter and central nodules are ...particularly difficult to visualize or palpate during surgery, thus nodule localization can be a difficult problem for the thoracic surgeon. Although minimally invasive techniques including transthoracic CT and bronchoscopic guided biopsy may establish a diagnosis, these methods do not help locate nodules during surgery and can lead to inadequate tissue sampling. Therefore, surgical biopsy is often required for diagnosis and management of SPNs. Additionally, after an excision, intraoperative margin assessment is important to prevent local recurrence. This is important for bronchial margins following lobectomy or parenchymal margins following sublobar resection. First, we will examine methods of preoperative lesion marking, including wire placement, dye marking, ultrasound, fluoroscopy, and molecular imaging. Second, we will describe the current state-of-the-art in intraoperative margin assessment techniques.
Follow the Glow Singhal, Sunil, MD
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
09/2017, Volume:
154, Issue:
3
Journal Article
Over 80,000 people undergo pulmonary resection for a lung nodule in the United States each year. Small nodules are frequently missed or difficult to find despite preoperative imaging. We hypothesized ...that near-infrared (NIR) imaging technology could be used to identify and locate lung nodules during surgery.
We enrolled 18 patients who were diagnosed with a pulmonary nodule that required resection. All patients had a fine-cut 1-mm computed tomography scan preoperatively. The patients were given systemic 5 mg/kg indocyanine green and then underwent an open thoracotomy 24 hours later. The NIR imaging was used to identify the primary nodule and search for additional nodules that were not found by visual inspection or manual palpation of the ipsilateral lung.
Manual palpation and visual inspection identified all 18 primary pulmonary nodules and no additional lesions. Intraoperative NIR imaging detected 16 out of the 18 primary nodules. The NIR imaging also identified 5 additional subcentimeter nodules; 3 metastatic adenocarcinomas and 2 metastatic sarcomas. This technology could identify nodules as small as 0.2 cm and as deep as 1.3 cm from the pleural surface. This approach discovered 3 nodules that were in different lobes than the primary tumor. Nodule fluorescence was independent of size, metabolic activity, histology, tumor grade and vascularity.
This is the first-in-human demonstration of identifying pulmonary nodules during thoracic surgery with NIR imaging without a priori knowledge of their location or existence. The NIR imaging can detect pulmonary nodules during lung resections that are poorly visualized on computed tomography and difficult to discriminate on finger palpation.
Introduction
Cancer surgery has multiple challenges including localizing small lesions, ensuring negative margins, and identifying synchronous cancers. One of the tools proposed to address these ...issues is intraoperative molecular imaging (IMI). An important consideration in IMI is the quantification of the tumor fluorescence during the procedure and using that data to add clinical value. Currently, the most commonly cited measure of quantification is the tumor-to-background ratio (TBR). Our goal was to evaluate the clinical value of TBR measured with OTL38 NIR tracer during a lung cancer resection.
Methods
Intraoperative data was retrospectively reviewed from a prospectively collected 5-year database. Between 2015 and 2020, 279 patients were included in the study. For standardization, all patients underwent infusion of the same targeted molecular optical contrast agent (OTL38) for lung cancer resections; then, the mean fluorescence intensity of the tumors and background tissues were calculated. To evaluate the clinical efficacy of the TBR calculation, the results were correlated with patient, biologic, tumor, and technological factors.
Results
For pulmonary surgery, patient factors such as gender, age, smoking history, and time from infusion of OTL38 to surgery did not have any statistical significance in predicting the TBR during surgery. In addition, TBR measurements did not correlate with location of the tumor in the lung (
p
= 0.123). There was no statistical correlation of preoperative positron emission tomography measurements (standardized uptake value) with intraoperative TBR. However, there was statistically significant negative correlation of
in situ
TBR measurement and the distance of the lesion from the surface of the organ (
p
< 0.001). Adenocarcinoma spectrum lesions overall had statistically significant correlation with
in situ
fluorescence compared to other NSCLC malignancies (
p
< 0.01) but TBR measurements could not identify histopathologic subtype on univariate analysis (
p
= 0.089). There was a tendency for
in situ
fluorescence for moderately and well-differentiated adenocarcinoma spectrum lesions, but this was not statistically significant. When comparing the
in situ
TBR of benign to malignant nodules in the lung, there was no statistically significant association (
p
= 0.145). In subset analysis, adenocarcinoma spectrum lesions tend to fluoresce at brighter with OTL38 compared to other histologic subtypes.
Conclusion
In our various iterations, the results of our retrospective analysis did not show that TBR measurements during OTL38-guided surgery provide clinically useful information about the nature of the nodule or cancer. The true value of IMI is in the ability for the surgeon to use the fluorescence to guide the surgeon to the tumor and margins, but that sophisticated quantification of the amount of fluorescence may not have clinical utility.
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.
Because the most reliable therapy for cancer involves quantitative resection of all diseased tissue, considerable effort has been devoted to improving a surgeon’s ability to locate and remove all ...malignant lesions. With the aid of improved optical imaging equipment, we and others have focused on developing tumor-targeted fluorescent dyes to selectively illuminate cancer nodules during surgery. We describe here the design, synthesis, optical properties, in vitro and in vivo tumor specificity/affinity, pharmacokinetics, preclinical toxicology, and some clinical application of a folate receptor (FR)-targeted NIR dye (OTL38) that concentrates specifically in cancer tissues and clears rapidly from healthy tissues. We demonstrate that OTL38 binds FR-expressing cells with ∼1 nM affinity and eliminates from receptor negative tissues with a half-time of <30 min. We further show that OTL38 enables visualization of malignant lesions at concentrations less than 100-fold those required to elicit signs of toxicity. Since OTL38 also provides excellent tumor contrast in both murine tumor models and human cancer patients, we conclude that OTL38 constitutes an excellent NIR dye for fluorescence-guided resection of malignant lesions in cancer patients.
Fluorescence-guided surgery has emerged as a powerful tool to detect, localize and resect tumors in the operative setting. Our laboratory has pioneered a novel way to administer an FDA-approved ...near-infrared (NIR) contrast agent to help surgeons with this task. This technique, coined Second Window ICG, exploits the natural permeability of tumor vasculature and its poor clearance to deliver high doses of indocyanine green (ICG) to tumors. This technique differs substantially from established ICG video angiography techniques that visualize ICG within minutes of injection. We hypothesized that Second Window ICG can provide NIR optical contrast with good signal characteristics in intracranial brain tumors over a longer period of time than previously appreciated with ICG video angiography alone. We tested this hypothesis in an intracranial mouse glioblastoma model, and corroborated this in a human clinical trial.
Intracranial tumors were established in 20 mice using the U251-Luc-GFP cell line. Successful grafts were confirmed with bioluminescence. Intravenous tail vein injections of 5.0 mg/kg (high dose) or 2.5 mg/kg (low dose) ICG were performed. The Perkin Elmer IVIS Spectrum (closed field) was used to visualize NIR fluorescence signal at seven delayed time points following ICG injection. NIR signals were quantified using LivingImage software. Based on the success of our results, human subjects were recruited to a clinical trial and intravenously injected with high dose 5.0 mg/kg. Imaging was performed with the VisionSense Iridium (open field) during surgery one day after ICG injection.
In the murine model, the NIR signal-to-background ratio (SBR) in gliomas peaks at one hour after infusion, then plateaus and remains strong and stable for at least 48 hours. Higher dose 5.0 mg/kg improves NIR signal as compared to lower dose at 2.5 mg/kg (SBR = 3.5 vs. 2.8; P = 0.0624). Although early (≤ 6 hrs) visualization of the Second Window ICG accumulation in gliomas is stronger than late (≥24 hrs) visualization (SBR = 3.94 vs. 2.32; p<0.05) there appears to be a long plateau period of stable ICG NIR signal accumulation within tumors in the murine model. We call this long plateau period the "Second Window" of ICG. In glioblastoma patients, the delayed visualization of intratumoral NIR signal was strong (SBR 7.50 ± 0.74), without any significant difference within the 19 to 30 hour visualization window (R2 = 0.019).
The Second Window ICG technique allows neurosurgeons to deliver NIR optical contrast agent to human glioblastoma patients, thus providing real-time tumor identification in the operating room. This nonspecific tumor accumulation of ICG within the tumor provides strong signal to background contrast, and is not significantly time dependent between 6 hours to 48 hours, providing a broad plateau for stable visualization. This finding suggests that optimal imaging of the "Second Window of ICG" may be within this plateau period, thus providing signal uniformity across subjects.
Surgery is currently the most effective and widely used procedure in treating human cancers, and the single most important predictor of patient survival is a complete surgical resection. Major ...opportunities exist to develop new and innovative technologies that could help the surgeon to delineate tumor margins, to identify residual tumor cells and micrometastases, and to determine if the tumor has been completely removed. Here we discuss recent advances in nanotechnology and optical instrumentation, and how these advances can be integrated for applications in surgical oncology. A fundamental rationale is that nanometer-sized particles such as quantum dots and colloidal gold have functional and structural properties that are not available from either discrete molecules or bulk materials. When conjugated with targeting ligands such as monoclonal antibodies, peptides, or small molecules, these nanoparticles can be used to target malignant tumor cells and tumor microenvironments with high specificity and affinity. In the "mesoscopic" size range of 10-100 nm, nanoparticles also have large surface areas for conjugating to multiple diagnostic and therapeutic agents, opening new possibilities in integrated cancer imaging and therapy.
Pulmonary metastasectomy is widely accepted for many tumor types because it may prolong survival and potentially cure some patients. However, intraoperative localization of pulmonary metastases can ...be technically challenging. We propose that intraoperative near-infrared (NIR) molecular imaging can be used as an adjunct during disease localization.
We inoculated 50 C57BL/6 mice with Lewis lung carcinoma (LLC) flank tumors. After flank tumor growth, mice were injected through the tail vein with indocyanine green (ICG) before operation, and intraoperative imaging was used to detect pulmonary metastases. On the basis of these experiments, we enrolled 8 patients undergoing pulmonary metastasectomy into a pilot and feasibility clinical trial. Each patient received intravenous ICG 1 day before operation, followed by wedge or segmental resection. Samples were imaged on the back table with an NIR camera to confirm disease presence and margins. All murine and human tumors and margins were confirmed by pathologic examination.
Mice had an average of 4 ± 2 metastatic tumors on both lungs, with an average size of 5.1 mm (interquartile range IQR 2.2 mm to 7.6 mm). Overall, 200 of 211 (95%) metastatic deposits were markedly fluorescent, with a mean tumor-to-background ratio (TBR) of 3.4 (IQR 3.1 to 4.1). The remaining tumors had a TBR below 1.5. In the human study, intraoperative NIR imaging identified six of the eight preoperatively localized lesions. Intraoperative back table NIR imaging identified all metastatic lesions, which were confirmed by pathologic examination. The average tumor size was 1.75 ± 1.4 cm, and the mean ex vivo TBR was 3.3 (IQR 3.1 to 3.7). Pathologic examination demonstrated melanoma (n = 4), osteogenic sarcoma (n = 2), renal cell carcinoma (n = 2), chondrosarcoma (n = 1), leiomyosarcoma (n = 1), and colorectal carcinoma (n = 1).
Systemic ICG identifies subcentimeter tumor metastases to the lung in murine models, and this work provides proof of principle in humans. Future research is focused on improving depth of penetration into the lung parenchyma.
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