Latisha A. Smith

Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update.

Near-infrared (NIR) fluorescence imaging clinical studies have been reported in the literature with six different devices that employ various doses of indocyanine green (ICG) as a non-specific contrast agent. To date, clinical applications range from (i) angiography, intraoperative assessment of vessel patency, and tumor/metastasis delineation following intravenous administration of ICG, and (ii) imaging lymphatic architecture and function following subcutaneous and intradermal ICG administration. In the latter case, NIR fluorescence imaging may enable new discoveries associated with lymphatic function due to (i) a unique niche that is not met by any other conventional imaging technology and (ii) its exquisite sensitivity enabling high spatial and temporal resolution. Herein, we (i) review the basics of clinical NIR fluorescence imaging, (ii) survey the literature on clinical application of investigational devices using ICG fluorescent contrast, (iii) provide an update of non-invasive dynamic lymphatic imaging conducted with our FDPM device, and finally, (iv) comment on the future NIR fluorescence imaging for non-invasive and intraoperative use given recent demonstrations showing capabilities for imaging following microdose administration of contrast agent.

Assessment of Lymphatic Contractile Function After Manual Lymphatic Drainage Using Near-Infrared Fluorescence Imaging

OBJECTIVE To investigate the feasibility of assessing the efficacy of manual lymphatic drainage (MLD), a method for lymphedema (LE) management, by using near-infrared (NIR) fluorescence imaging. DESIGN Exploratory pilot study. SETTING Primary care unit. PARTICIPANTS Subjects (N=10; age, 18-68y) with a diagnosis of grade I or II LE and 12 healthy control subjects (age, 22-59y). INTERVENTION Indocyanine green (25 μg in 0.1 mL each) was injected intradermally in bilateral arms or legs of subjects. Diffused excitation light illuminated the limbs, and NIR fluorescence images were collected by using custom-built imaging systems. Subjects received MLD therapy, and imaging was performed pre- and posttherapy. MAIN OUTCOME MEASURES Apparent lymph velocities and periods between lymphatic propulsion events were computed from fluorescence images. Data collected pre- and post-MLD were compared and evaluated for differences. RESULTS By comparing pre-MLD lymphatic contractile function against post-MLD lymphatic function, results showed that average apparent lymph velocity increased in both the symptomatic (+23%) and asymptomatic (+25%) limbs of subjects with LE and control limbs (+28%) of healthy subjects. The average lymphatic propulsion period decreased in symptomatic (-9%) and asymptomatic (-20%) limbs of subjects with LE, as well as in control limbs (-23%). CONCLUSIONS We showed that NIR fluorescence imaging could be used to quantify immediate improvement of lymphatic contractile function after MLD.

Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema

Lymphedema affects up to 50% of all breast cancer survivors. Management with pneumatic compression devices (PCDs) is controversial, owing to the lack of methods to directly assess benefit. This pilot study employed an investigational, near-infrared (NIR) fluorescence imaging technique to evaluate lymphatic response to PCD therapy in normal control and breast cancer-related lymphedema (BCRL) subjects. Lymphatic propulsion rate, apparent lymph velocity, and lymphatic vessel recruitment were measured before, during, and after advanced PCD therapy. Lymphatic function improved in all control subjects and all asymptomatic arms of BCRL subjects. Lymphatic function improved in 4 of 6 BCRL affected arms, improvement defined as proximal movement of dye after therapy. NIR fluorescence lymphatic imaging may be useful to directly evaluate lymphatic response to therapy. These results suggest that PCDs can stimulate lymphatic function and may be an effective method to manage BCRL, warranting future clinical trials.

Hyperbaric Oxygen Therapy for Severe Ulcerative Colitis

Hyperbaric oxygen therapy has been used to successfully treat perineal Crohns disease. We describe the first successful use of hyperbaric oxygen therapy in the treatment of ulcerative colitis, refractory to conventional therapies. Therapy consisted of 30 courses of 100% oxygen at a pressure of 2.0 atm absolute. Clinical remission was achieved on the basis of the Truelove-Witts and disease activity index scores. Corticosteroids were successfully tapered off once remission was achieved.

Lymphatic abnormalities in the normal contralateral arms of subjects with breast cancer-related lymphedema as assessed by near-infrared fluorescent imaging

Current treatment of unilateral breast cancer-related lymphedema (BCRL) is only directed to the afflicted arm. Near-infrared fluorescent imaging (NIRF) of arm lymphatic vessel architecture and function in BCRL and control subjects revealed a trend of increased lymphatic abnormalities in both the afflicted and unafflicted arms with increasing time after lymphedema onset. These pilot results show that BCRL may progress to affect the clinically “normal” arm, and suggest that cancer-related lymphedema may become a systemic, rather than local, malady. These findings support further study to understand the etiology of cancer-related lymphedema and lead to better diagnostics and therapeutics directed to the systemic lymphatic system.

Dying to play video games: carbon monoxide poisoning from electrical generators used after hurricane Ike.

BACKGROUND. Carbon monoxide (CO) poisoning is common after major storms because of loss of electrical power and use of alternate fuel sources for heat and electricity. In past epidemics of hurricane-related CO poisoning, the source has typically been gasoline-powered electrical generators. Although it is typically believed that generators were used to power air conditioning and refrigeration, this report demonstrates an unsuspected reason for their use. PATIENTS AND METHODS. After Hurricane Ikes landfall in September 2008, major power outages were associated with an epidemic of CO poisoning from electrical generators, as expected. Staff at Memorial Hermann Hospital-Texas Medical Center treated or telephone-triaged cases from the Houston area. A review of the details of those cases forms the basis of this report. RESULTS. Memorial Hermann Hospital-Texas Medical Center staff treated or triaged 37 individuals exposed to CO from gasoline-powered electrical generators in 13 incidents in the first 36 hours after landfall of the hurricane. Notably, 54% (20 of 37) of the patients were under the age of 18 years. Symptoms ranged from mild to severe, with 1 child dying at the scene. Eleven patients were treated with hyperbaric oxygen. Among 9 incidents in which the reason for generator use was determined, 5 were due to generators powering video games or televisions to watch movies or programs. These 5 incidents in which video games were being powered accounted for 75% (15 of 20) of the pediatric poisonings. CONCLUSIONS. Generator-related CO poisoning is indeed common during power outages after hurricanes. However, generators are commonly being used to provide electricity to power entertainment devices for children, such as video games. Additional public education about CO risk is needed, perhaps directed at older children and teenagers through the schools in regions susceptible to hurricanes.

Near-infrared fluorescence imaging of lymphatics in head and neck lymphedema

Treatment of lymphatic disease is complicated and controversial, due in part to the limited understanding of the lymphatic system. Lymphedema (LE) is a frequent complication after surgical resection and radiation treatment in cancer survivors, and is especially debilitating in regions where treatment options are limited. Although some extremity LE can be effectively treated with manual lymphatic drainage (MLD) therapy or compression devices to direct proximal lymph transport, head and neck LE is more challenging, due to complicated geometry and complex lymphatic structure in head and neck region. Herein, we describe the compassionate use of an investigatory technique of near-infrared (NIR) fluorescence imaging to understand the lymphatic anatomy and function, and to help direct MLD in a patient with head and neck LE. Immediately after 9 intradermal injections of 25 μg indocyanine green each around the face and neck region, NIR fluorescence images were collected using a custom-built imaging system with diffused excitation light illumination. These images were then used to direct MLD therapy. In addition, 3-dimensional (3D) surface profilometry was used to monitor response to therapy. NIR fluorescence images of functioning lymphatic vessels and abnormal structures were obtained. Precise geometries of facial structures were obtained using 3D profilometry, and detection of small changes in edema between therapy sessions was achieved. NIR fluorescence imaging provides a mapping of lymphatic architecture to direct MLD therapy and thus improve treatment efficacy in the head and neck LE, while 3D profilometry allowed longitudinal assessment of edema to evaluate the efficacy of therapy.

Validation of ALFIA: A platform for quantifying near-infrared fluorescent images of lymphatic propulsion in humans

Recently, we demonstrated near-infrared (NIR) fluorescence imaging for quantifying real-time lymphatic propulsion in humans following intradermal injections of microdose amounts of indocyanine green. However computational methods for image analysis are underdeveloped, hindering the translation and clinical adaptation of NIR fluorescent lymphatic imaging. In our initial work we used ImageJ and custom MatLab programs to manually identify lymphatic vessels and individual propulsion events using the temporal transit of the fluorescent dye. In addition, we extracted the apparent velocities of contractile propagation and time periods between propulsion events. Extensive time and effort were required to analyze the 6-8 gigabytes of NIR fluorescent images obtained for each subject. To alleviate this bottleneck, we commenced development of ALFIA, an integrated software platform which will permit automated, near real-time analysis of lymphatic function using NIR fluorescent imaging. However, prior to automation, the base algorithms calculating the apparent velocity and period must be validated to verify that they produce results consistent with the proof-of-concept programs. To do this, both methods were used to analyze NIR fluorescent images of two subjects and the number of propulsive events identified, the average apparent velocities, and the average periods for each subject were compared. Paired Students t-tests indicate that the differences between their average results are not significant. With the base algorithms validated, further development and automation of ALFIA can be realized, significantly reducing the amount of user interaction required, and potentially enabling the near real-time, clinical evaluation of NIR fluorescent lymphatic imaging.

NIR Fluorescence Imaging for in vivo Assessment of Normal and Diseased Lymphatics

Near-infrared fluorescence imaging with microdose indocyanine green was used to visualize the normal and diseased lymphatic structure and quantify the lymphatic function in vivo. Lymphatic function was significantly improved after manual lymphatic drainage.

Abstract 4331: Assessment of cancer-related lymphatic impairment using NIR fluorescent imaging

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The lymphatic system contributes a major pathway for cancer metastasis and, through lymph node biopsy, provides the primary prognostic factor guiding therapy post-operative cancer patients. However, survivorship and quality of life for cancer survivors who undergo lymph node dissection can be complicated by lymphedema (LE). The etiology of LE is unknown and in this study, we developed methods to image lymphatic structure and function and its response to LE treatment to gain new understandings of the disease. Twenty unilateral LE and 24 normal control subjects were recruited in an IRB and FDA approved, Phase 0 exploratory trial. Onset of LE occurred after cancer treatment in 13 of the 20 LE subjects. Total dose of less than 400 µg of indocyanine green was injected intradermally in bilateral arms or legs. Immediately after the injections, a diffused excitation light illuminated the limbs and NIR fluorescence images were obtained using custom-built imaging systems. Twenty-two of the 44 subjects received the only accepted, but controversial therapy for LE, manual lymph drainage (MLD). Images were obtained immediately before and after MLD. Apparent lymph velocities and periods between lymphatic propulsion events were computed from fluorescence images. Images show dramatically different architecture of lymphatics between control normal and LE subjects. Well defined and organized lymphatic structures as well as active propulsions of lymph “packets” were commonly seen in normal limbs. In LE limbs, however, extravascular dye accumulation, networks of lymphatic capillaries, tortuous lymphatic vessels, and fewer propulsions were seen. The results without or before MLD show that the apparent velocity and periods between propulsions in average are 0.79 cm/s and 48.2 s for control arms and 0.94 cm/s and 52.2 s for control legs; 0.90 cm/s and 33.2 s for symptomatic arms and 0.78 cm/s and 72.1 s for symptomatic legs in LE subjects; 0.79 cm/s and 39.6 s for asymptomatic arms and 0.83 cm/s and 65.3 s for asymptomatic legs in LE subjects. In addition, an increase in velocity and a decrease in propulsion period were seen in the improvement of lymphatic function following MLD in subjects who received treatment. MLD resulted in increased apparent lymph velocities in the symptomatic (+23%) and asymptomatic (+25%) limbs of LE subjects and in the control limbs (+28%) of normal subjects. The lymphatic propulsion periods decreased in the symptomatic (−9%) and asymptomatic (−20%) limbs of LE subjects, and in the control limbs (−23%). NIR fluorescent imaging allows the in vivo visualization of the lymphatics architecture and quantification of lymphatic function. It could be used not only to study the impairment of lymphatic function after cancer surgery but also to direct treatment of LE subjects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4331.