Denis M. Gilmore

Identification of metastatic nodal disease in a phase 1 dose-escalation trial of intraoperative sentinel lymph node mapping in non–small cell lung cancer using near-infrared imaging

OBJECTIVES Early-stage non-small cell lung cancer (NSCLC) has a high recurrence rate and poor 5-year survival, particularly if lymph nodes are involved. Our objective was to perform a dose-escalation study to assess safety and feasibility of intraoperative near-infrared (NIR) fluorescence imaging to identify the first tumor-draining lymph nodes (ie, sentinel lymph nodes [SLNs] in patients with NSCLC). METHODS A-dose escalation phase 1 clinical trial assessing real-time NIR imaging after peritumoral injection of 3.8 to 2500 μg indocyanine green (ICG) was initiated in patients with suspected stage I/II NSCLC. Visualization of lymphatic migration, SLN identification, and adverse events were recorded. RESULTS Thirty-eight patients underwent ICG injection and NIR imaging via thoracotomy (n = 18) or thoracoscopic imaging (n = 20). SLN identification increased with ICG dose, with fewer than 25% SLNs detected in dose cohorts of 600 μg or less versus 89% success at 1000 μg or greater. Twenty-six NIR(+) SLNs were identified in 15 patients, with 7 NIR(+) SLNs (6 patients) harboring metastatic disease on histologic analysis. Metastatic nodal disease was never identified in patients with a histologically negative NIR(+) SLN. No adverse reactions were noted. CONCLUSIONS NIR-guided SLN identification with ICG was safe and feasible in this initial dose-escalation trial. ICG doses greater than 1000 μg yielded nearly 90% intrathoracic SLN visualization, with the presence or absence of metastatic disease in the SLN directly correlating with final nodal status of the lymphadenectomy specimen. Further studies are needed to optimize imaging parameters and confirm sensitivity and specificity of SLN mapping in NSCLC using this promising imaging technique.

Prevention of nodal metastases in breast cancer following the lymphatic migration of paclitaxel-loaded expansile nanoparticles.

Although breast cancer patients with localized disease exhibit an excellent long-term prognosis, up to 40% of patients treated with local resection alone may harbor occult nodal metastatic disease leading to increased locoregional recurrence and decreased survival. Given the potential for targeted drug delivery to result in more efficacious locoregional control with less morbidity, the current study assessed the ability of drug-loaded polymeric expansile nanoparticles (eNP) to migrate from the site of tumor to regional lymph nodes, locally deliver a chemotherapeutic payload, and prevent primary tumor growth as well as lymph node metastases. Expansile nanoparticles entered tumor cells and paclitaxel-loaded eNP (Pax-eNP) exhibited dose-dependent cytotoxicity in vitro and significantly decreased tumor doubling time in vivo against human triple negative breast cancer in both microscopic and established murine breast cancer models. Furthermore, migration of Pax-eNP to axillary lymph nodes resulted in higher intranodal paclitaxel concentrations and a significantly lower incidence of lymph node metastases. These findings demonstrate that lymphatic migration of drug-loaded eNP provides regionally targeted delivery of chemotherapy to both decrease local tumor growth and strategically prevent the development of nodal metastases within the regional tumor-draining lymph node basin.

A novel technique for tumor localization and targeted lymphatic mapping in early-stage lung cancer

Objective: To investigate safety and feasibility of navigational bronchoscopy (NB)‐guided near‐infrared (NIR) localization of small, ill‐defined lung lesions and sentinel lymph nodes (SLN) for accurate staging in patients with non–small cell lung cancer (NSCLC). Methods: Patients with known or suspected stage I NSCLC were enrolled in a prospective pilot trial for lesion localization and SLN mapping via NB‐guided NIR marking. Successful localization, SLN detection rates, histopathologic status of SLN versus overall nodes, and concordance to initial clinical stage were measured. Ex vivo confirmation of NIR+ SLNs and adverse events were recorded. Results: Twelve patients underwent NB‐guided marking with indocyanine green of lung lesions ranging in size from 0.4 to 2.2 cm and located 0.1 to 3 cm from the pleural surface. An NIR+ “tattoo” was identified in all cases. Ten patients were diagnosed with NSCLC and 9 SLNs were identified in 8 of the 10 patients, resulting in an 80% SLN detection rate. SLN pathologic status was 100% sensitive and specific for overall nodal status with no false‐negative results. Despite previous nodal sampling, one patient was found to have metastatic disease in the SLN alone, a 12.5% rate of disease upstaging with NIR SLN mapping. SLN were detectable for up to 3 hours, allowing time for obtaining a tissue diagnosis and surgical resection. There were no adverse events associated with NB‐labeling or indocyanine green dye itself. Conclusions: NB‐guided NIR lesion localization and SLN identification was safe and feasible. This minimally invasive image‐guided technique may permit the accurate localization and nodal staging of early stage lung cancers.

Developing intrathoracic sentinel lymph node mapping with near-infrared fluorescent imaging in non–small cell lung cancer

With poor survival and high recurrence rates, early-stage lung cancer currently appears to be understaged or undertreated, or both. Although sentinel lymph node biopsy is standard for patients with breast cancer and melanoma, its success has been unreliable in non-small cell lung cancer. Sentinel lymph node biopsy might aid in the identification of lymph nodes at the greatest risk of metastasis and allow for more detailed analysis to select for patients who might benefit from adjuvant therapy. The early results in our recent clinical trial of patients with early-stage lung cancer have suggested that near-infrared imaging might offer a platform for reliable sentinel lymph node identification in these patients.

Preclinical study of near-infrared-guided sentinel lymph node mapping of the porcine lung.

BACKGROUND The presence of lymph node metastasis is the most important prognostic factor in early non-small cell lung cancer. Our objective was to develop a rapid, simple, and reliable method for thoracic sentinel lymph node (SLN) identification using near-infrared fluorescence imaging and clinically available contrast agents. METHODS Indocyanine green (ICG) reconstituted in saline, human serum albumin, human fresh frozen plasma, and autologous porcine plasma was evaluated for optimal formulation and dosing for SLN within porcine lungs. Animals were imaged using the fluorescence-assisted resection and exploration for surgery imaging system. The SLN identification rate, time to identification and fluorescence intensity of the SLN, bronchus, and background were measured. RESULTS The SLN identification rates varied widely, ranging from 33% to 100% as a function of the carrier used for ICG reconstitution. No significant difference was noted in SLN fluorescence intensity; however, bronchial intensity was significantly higher with ICG: albumin, which resulted in the lowest rate of SLN identification. Subsequent evaluation with 125 μM and 250 μM ICG:porcine plasma resulted in identification of strongly fluorescent SLNs, with identification rates of 93% and 100% and median signal-to-background ratios of 8.5 and 12.15, respectively, in less than 2 minutes in situ. CONCLUSIONS Near-infrared fluorescence imaging with ICG is a reliable method for SLN mapping in the lung with high sensitivity. Mixing of ICG with plasma resulted in strong SLN fluorescence signal with reliable identification rates.

Tumor Targeted Nanoparticles: A Modern Day Trojan Horse

During the past few decades, particles of various compositions have been engineered in ever smaller sizes to function in both diagnostic and therapeutic capacities. Nanoparticles are now available on a scale similar to many biological molecules and infectious agents, thereby opening the possibility of biological intervention on the molecular level. Several recent timely reports summarize nanoparticle properties and potential clinical applications in early-stage clinical trials.

Long-term outcomes after near-infrared sentinel lymph node mapping in non–small cell lung cancer

Objective: To report the first analysis of long‐term outcomes using near‐infrared (NIR) image‐guided sentinel lymph node (SLN) mapping in non–small cell lung cancer (NSCLC). Methods: Retrospective analysis of patients with NSCLC enrolled in 2 prospective phase 1 NIR‐guided SLN mapping trials, including an indocyanine green (ICG) dose‐escalation trial, was performed. All patients underwent NIR imaging for SLN identification followed by multistation mediastinal lymph node sampling (MLNS) and pathologic assessment. Disease‐free (DFS) and overall survival (OS) were compared between patients with NIR+ SLN (SLN group) and those without (non‐SLN group). Results: SLN detection, recurrence, DFS, and OS were assessed in 42 patients with NSCLC who underwent intraoperative peritumoral ICG injection, NIR imaging, and MLNS. NIR+ SLNs were identified in 23 patients (SLN group), whereas SLNs were not identified in 19 patients enrolled before ICG dose and camera optimization (non‐SLN group). Median follow‐up was 44.5 months. Pathology from NIR+ SLNs was concordant with overall nodal status in all 23 patients. Sixteen patients with SLN were deemed pN0 and no recurrences were, whereas 4 of 15 pN0 non‐SLN patients developed nodal or distant recurrent disease. Comparing SLN versus non‐SLN pN0 patients, the probability of 5‐year OS is 100% versus 70.0% (P = .062) and 5‐year DFS is statistically significantly improved at 100% versus 66.1% (P = .036), respectively. Among the 11 pN+ patients, 7 were in the SLN group, with >40% showing metastases in the SLN alone. Conclusions: Patients with pN0 SLNs showed favorable disease‐free and overall survival. This preliminary review of NIR SLN mapping in NSCLC suggests that pN0 SLNs may better represent true N0 status. A larger clinical trial is planned to validate these findings.

Recurrent chylous pericardial effusion and left neck mass.

We present a case of a woman initially presenting with a neck mass and subsequently found to have generalized lymphatic anomaly with diffuse lymphatic dilation and proliferation involving the mediastinum and pericardium. Intrathoracic involvement of generalized lymphatic anomalies can lead to recurrent pleural effusions, pericardial effusions, and severe respiratory infections. These anomalies cannot be cured and significantly impact quality of life. Multidisciplinary involvement is crucial to maximize symptom relief as surgery to remove lymphatics can be morbid and the disease is usually recurrent.