Effective low-dose escalation of indocyanine green for near-infrared fluorescent sentinel lymph node mapping in melanoma.

BACKGROUND: Regional lymph node metastasis is the strongest prognostic factor in patients with melanoma. Published reports that used lymphoscintigraphy with radioactive colloids and blue dye demonstrated accurate sentinel lymph node (SLN) identification in inguinal nodes and axillary nodes, but decreased accuracy in cervical, popliteal, epitrochlear, and parascapular nodes. Near-infrared imaging (NIR) may utilize indocyanine green (ICG) to improve SLN identification. The safety, feasibility and optimal dose of albumin-bound ICG (ICG:HSA) was assessed by NIR to improve SLN mapping in patients with melanoma. METHODS: Twenty-five consecutive patients with biopsy-proven melanoma underwent standard SLN mapping with preoperatively administered technetium-99 m nanocolloid (Tc-99 m). Intraoperative NIR fluorescence imaging was performed after injection of 1.0 ml of 100, 250 or 500 µM of ICG:HSA in four quadrants around the primary lesion. RESULTS: NIR fluorescent imaging demonstrated accuracy of 98 % when compared with radioactive colloid. A total of 65 lymph nodes were identified (65 with Tc-99 m, 64 with ICG:HSA). Overall, successful mapping that used either technique was 96 % as one patient failed to map with either modality. As the dose of ICG was increased, the signal-to-background ratio increased from a median of 3.1 to 8.4 to 10.9 over the range of 100, 250, and 500 µM, respectively. CONCLUSIONS: SLN mapping with ICG:HSA is feasible and accurate in melanoma. ICG has the added advantage of a low cost and an intraoperative technique that does not alter the surgical field, thus allowing for easy identification of SLNs.

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.

Long-Term Physical HRQOL Decreases After Single Lung as Compared With Double Lung Transplantation.

BACKGROUND: Single lung transplantation (SLT) and double lung transplantation (DLT) are associated with differences in morbidity and mortality, although the effects of transplant type on patient-reported outcomes are not widely reported and conclusions have differed. Previous studies compared mean health-related quality of life (HRQOL) scores but did not evaluate potentially different temporal trajectories in the context of longitudinal follow-up. To address this uncertainty, this study was designed to evaluate longitudinal HRQOL after SLT and DLT with the hypothesis that temporal trajectories differ between SLT and DLT. METHODS: Patients transplanted at a single institution were eligible to be surveyed at 1 month, 3 months, 6 months, and then annually after transplant using the Short Form 36 Health Survey, with longitudinal physical component summary (PCS) and mental component summary (MCS) scores as the primary outcomes. Multivariable mixed-effects models were used to evaluate the effects of transplant type and time posttransplant on longitudinal PCS and MCS after adjusting age, diagnosis, rejection, Lung Allocation Score quartile, and intubation duration. Time by transplant type interaction effects were used to test whether the temporal trajectories of HRQOL differ between SLT and DLT recipients. HRQOL scores were referenced to general population norms (range, 40 to 60; mean, 50 ± 10) using accepted standards for a minimally important difference (½ SD, 5 points). RESULTS: Postoperative surveys (n = 345) were analyzed for 136 patients (52% male, 23% SLT, age 52 ± 13 years, LAS 42 ± 12, follow-up 37 ± 29 months [range, 0.6 to 133]) who underwent lung transplantation between 2005 and 2016. After adjusting for model covariates, overall posttransplant PCS scores have a significant downward trajectory (p = 0.015) whereas MCS scores remain stable (p = 0.593), with both averaging within general population norms. The time by transplant type interaction effect (p = 0.002), however, indicate that posttransplant PCS scores of SLT recipients decline at a rate of 2.4 points per year over the total observation period compared to DLT. At approximately 60 months, the PCS scores of SLT recipients, but not DLT recipients, fall below general population norms. CONCLUSIONS: The trajectory of physical HRQOL in patients receiving SLT declines over time compared with DLT, indicating that, in the longer term, SLT recipients are more likely to have physical HRQOL scores that fall substantively below general population norms. Physical HRQOL after 5 years may be a consideration for lung allocation and patient counseling regarding expectations when recommending SLT or DLT.

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.

Safety and feasibility of near-infrared image-guided lymphatic mapping of regional lymph nodes in esophageal cancer.

OBJECTIVE: To assess safety and feasibility of an intraoperative, minimally invasive near-infrared (NIR) image-guided approach to lymphatic mapping in patients with esophageal cancer. METHODS: Although local lymph nodes (LNs) are removed with the esophageal specimen, no techniques are available to identify the regional LNs (separate from the esophagus) during esophagectomy. We hypothesize that NIR imaging can identify regional LNs with the potential to improve staging and guide the extent of lymphadenectomy. Nine of the 10 patients enrolled had resectable esophageal adenocarcinoma and underwent NIR mapping following peritumoral submucosal injection of indocyanine green (ICG) alone or premixed in human serum albumin (ICG:HSA) before resection. NIR imaging was performed in situ and ex vivo. RESULTS: In 6 of the 10 patients, intraoperative NIR imaging demonstrated an NIR signal at all tumors and in 2 to 6 NIR(+) regional LNs. NIR(+) LNs were not identified in 4 patients: 1 patient with occult stage IV disease, for whom further imaging was not performed and thus was excluded from analysis, and 3 patients in whom ICG was used without HSA. Identification of local LNs on the esophagus was obscured by a peritumoral background. Importantly, the pathological status of NIR(+) regional LNs reflected overall regional nodal status. CONCLUSIONS: NIR lymphatic mapping is safe and feasible in patients with esophageal cancer and can identify regional LNs when ICG:HSA is used. Although more work is needed to improve background signals and local LN identification, intraoperative detection of regional NIR(+) LNs allows an in-depth histological analysis of LN basins not commonly scrutinized as part of the specimen and may improve the detection of occult nodal disease.

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.

Timing is everything-colectomy performed on Monday decreases length of stay.

BACKGROUND: Perioperative care of patients undergoing colon resection requires a multidisciplinary approach by the operating surgeon, residents, and nurses. Operations performed on Monday take full advantage of hospital resources throughout the week to meet expected discharge by Friday. In a current health care environment of diminishing means, improving the timing of surgery in relation to expected length of stay may play an important role in preserving health care resources. METHODS: A retrospective review of a prospectively collected colorectal surgical database identified all patients who underwent segmental colon resection at a single tertiary care referral center from 2004 to 2010. Length of stay for patients undergoing elective open and minimally invasive segmental colectomy was compared for Monday versus Tuesday through the weekend. Patient and surgeon demographics were recorded as well as postoperative outcomes and complications. RESULTS: A total of 868 segmental colectomies were performed during the study period. Length of stay was significantly decreased by .73 days (P < .01) for all segmental colectomies performed on Monday compared with those performed Tuesday through Sunday. There was also a significant decrease in length of stay looking independently at right (.96 days, P < .01) and left or sigmoid colectomies (.56 days, P < .01). There was no significant difference in patient or surgeon demographics to account for this difference. CONCLUSIONS: Segmental colectomies have a significantly decreased length in stay when performed on Monday compared with the rest of the week. The decrease is independent of surgeon, comorbidities, and complications. This difference may be the result of patients' taking full advantage of hospital resources and ancillary support. Cost-effective measures may be evaluated and directed at adjustment of resources available throughout the week to reduce length of stay.

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.

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.

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.