Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.

The lymphatics play important roles in chronic diseases/conditions that comprise the bulk of healthcare worldwide. Yet the ability to routinely image and diagnose lymphatic dysfunction, using commonly available clinical imaging modalities, has been lacking and as a result, the development of effective treatment strategies suffers. Nearly two decades ago, investigational near-infrared fluorescence lymphatic imaging and ICG lymphography were developed as routine diagnostic for clinically evaluating, quantifying, and treating lymphatic dysfunction in cancer-related and primary lymphedema, chronic venous disease, and more recently, autoimmune and neurodegenerative disorders. In this review, we provide an overview of what these non-invasive technologies have taught us about lymphatic (dys) function and anatomy in human studies and in corollary animal studies of human disease. We summarize by commenting on new impactful clinical frontiers in lymphatic science that remain to be facilitated by imaging.

Evidence suggests lymphatic function mediates local rheumatoid arthritis (RA) flares. Yet biologics that target the immune system are dosed systemically via the subcutaneous (SC) administration route, thereby inefficiently reaching local lymphatic compartments. Nanotopography has previously been shown to disrupt tight cellular junctions, potentially enhancing local lymphatic delivery and potentially improving overall therapeutic efficacy. We first characterized nanotopography (SOFUSA™) delivery of an anti-TNF drug, etanercept, by comparing pharmacokinetic profiles to those obtained by conventional SC, intravenous (IV), and intradermal (ID) routes of administration, and assessed uptake of radiolabeled etanercept in draining lymph nodes (LNs) in single dosing studies. We then compared etanercept efficacy in a progressive rat model of collagen-induced arthritis (CIA), administered systemically via SC route of administration; via the regional lymphatics through ID delivery; or through a nanotopography (SOFUSA™) device at 10, 12, and 14 days post CIA induction. Measurements of hind limb swelling and near-infrared fluorescence (NIRF) imaging of afferent lymph pumping function and reflux were conducted on days 11, 13, and 18 post CIA induction and compared to untreated CIA animals. Univariate and multivariate analysis of variance were used to compare the group differences for percentage swelling and lymphatic contractile activity. Even though all three modes of administration delivered an equal amount of etanercept, SOFUSA™ delivery resulted in increased lymphatic pumping and significantly reduced swelling as compared to untreated, ID, and SC groups. Pharmacokinetic profiles in serum and LN uptake studies showed that using the nanotopography device resulted in the greatest uptake and retention in draining LNs. Locoregional lymphatic delivery of biologics that target the immune system may have more favorable pharmacodynamics than SC or IV administration. Nanotopography may provide a more efficient method for delivery of anti-TNF drugs to reverse impairment of lymphatic function and reduce swelling associated with RA flares.

Background: Understanding hospital-acquired pressure injury (HAPrI) etiology is essential for developing effective preventive interventions. Pressure injuries are classified based on the degree of visible tissue damage; the two most commonly identified HAPrI stages in critical care patients are stage 2 and deep tissue injury (DTI). Some experts speculate that stage 2 and DTI have different etiologies, with stage 2 injuries formed from the “outside in” as a result of tissue deformation, decreased perfusion, and subsequent ischemia caused by external pressure and/or shear forces, whereas DTI emerges from the “inside out” due to inadequate perfusion to the deeper tissues causing tissue ischemia. Objective: The purpose of this study was to compare risk profiles of intensive care unit (ICU) patients who developed stage 2 injuries versus DTIs. Methods: This was a retrospective cohort study to compare the risk profiles of patients in the ICU with stage 2 injuries and DTIs using electronic health record data. Eligible patients were admitted to the surgical or cardiovascular ICU at an academic medical center in the United States between 2014 and 2018. Anatomic locations were examined, and differences in anatomic patterns were compared using the χ2 test. Risk profile variables included demographic characteristics, Braden Scale scores, vasopressor infusions, hypotension, surgical factors, length of stay, BMI, laboratory values, diabetes, Charlson Comorbidity Index, and the levels of sedation or agitation. The distributions of potential risk variables between patients with stage 2 injuries and DTIs were summarized and compared. A logistic regression model with the least absolute shrinkage and selection operator method was developed to identify the critical risk factors for distinguishing stage 2 and DTI patients. Results: A total of 244 patients developed a stage 2 injury or DTI during the study period. Of those, 38 patients with medical device–related pressure injury were excluded. The final study sample consisted of 206 patients (n=146 stage 2 and n=60 DTI). Compared with DTIs, stage 2 HAPrIs were more likely to be located on a bony prominence (n=206, χ21=8.43, P=.03). The multivariate model showed that patients who developed stage 2 HAPrIs had a longer length of stay in the ICU than those with DTIs (odds ratio [OR] 1.001, 95% CI 1-1.002, P=.03) but were less likely than patients with DTIs to experience a diastolic blood pressure <50 mmHg (OR 0.179, 95% CI 0.072-0.416, P<.001) or receive an epinephrine infusion (OR 0.316, 95% CI 0.079-0.525, P=.008). Conclusions: Stage 2 injuries and DTIs have different risk factors and different anatomic patterns. Patients who developed DTIs were more likely to experience low diastolic blood pressure and receive epinephrine, a potent vasopressor. Stage 2 injuries were more likely to occur on the bony prominences, whereas DTIs commonly occurred on the fleshy parts of the body such as the buttock.