Lymphatic Research and Biology

Intracystic hemorrhage from lymphangiomas is a common phenomenon in lymphatic malformations (LMs); however, little is known about the associated compositional changes in the lymphatic fluid.

We prospectively collected lymphatic fluid from children with LMs. Lymphatic fluid was divided depending on the bleeding status into the bleeding and nonbleeding groups. The fluid was subjected to cytological and biochemical analyses to determine protein and cytokine levels. The Mann–Whitney U test was used to compare the two groups.

There were significant differences in the levels of interleukin (IL)-6, IL-10, and glucose, and the percentage of white blood cells between the bleeding and nonbleeding groups. There was no significant difference in chlorine and protein content; white blood cell count; and IL-2, IL-4, tumor necrosis factor α, and interferon γ levels between the two groups.

Lymphatic fluid is less stable in bleeding LMs than in non-bleeding LMs and is prone to inflammatory reactions. The inflammatory reaction in lymphatic fluid does not stimulate the cytokine storm in blood. The inflammatory reaction due to LMs does not affect the contents of protein and chlorine in lymphatic cyst fluid.

To determine the role of dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) in the management of postoperative chylothorax after lung cancer surgery.

Between July 2017 and November 2021, patients who developed postoperative chylothorax following pulmonary resection and mediastinal lymph node dissection were assessed and those who underwent DCMRL for the evaluation of chyle leak were evaluated. The findings of DCMRL and conventional lymphangiography were compared. The incidence of postoperative chylothorax was 0.9% (50/5587). Among the patients with chylothorax, a total of 22 patients (44.0% [22/50]; mean age, 67.6 ± 7.9 years; 15 men) underwent DCMRL. Treatment outcomes were compared between patients with conservative management (n = 10) and those with intervention (n = 12). The patients demonstrated unilateral pleural effusion, ipsilateral to the operation site, and showed right-sided dominance. The most frequent site of thoracic duct injury showing contrast media leakage was visualized at the subcarinal level. No DCMRL-related complication occurred. DCMRL showed comparable performance to conventional lymphangiography in visualizing the central lymphatics, including cisterna chyli (DCMRL vs. conventional lymphangiography, 72.7% vs. 45.5%, p = 0.25) and thoracic duct (90.9% vs. 54.5%, p = 0.13), and in localizing thoracic duct injury (90.9% vs. 54.5%, p = 0.13). On follow-up, the amount of chest tube drainage after lymphatic intervention showed a significant difference over time from that after medical treatment only (p = 0.02).

DCMRL can provide detailed information about the leak site and the central lymphatic anatomy in patients with chylothorax after lung cancer surgery. The findings of DCMRL can guide subsequent treatment planning for optimal outcomes.

Breast cancer-related lymphedema (BCRL) is a common complication of breast cancer treatment. Anecdotal and qualitative research suggests that heat and hot weather cause an exacerbation of BCRL; however, there is little quantitative evidence to support this. The aim of this article is to investigate the relationship between seasonal climate variation and limb size, volume, fluid distribution, and diagnosis in women following breast cancer treatment.

Women older than the age of 35 years who had undergone treatment for breast cancer were invited to participate. Twenty-five women aged between 38 and 82 years were recruited. Seventy-two percent received surgery, radiation therapy, and chemotherapy as part of their breast cancer treatment. Participants completed anthropometric, circumferential, and bioimpedance measures and a survey on three occasions: November (spring), February (summer), and June (winter). Diagnostic criteria of >2 cm and >200 mL difference between the affected and unaffected arm, and a positive bioimpedance ratio of >1.139 for a dominant arm and >1.066 for nondominant arm was applied across the three measurement occasions. No significant correlation between seasonal variation in climate and upper limb size, volume, or fluid distribution were found in women diagnosed with or at risk of developing BCRL. Lymphedema diagnosis depends on the season and diagnostic measurement tool utilized.

There was no statistically significant variation in limb size, volume, or fluid distribution in this population across spring, summer, and winter, although there were linked trends in these values. The diagnosis of lymphedema, however, varied between individual participants throughout the year. This has important implications for the implementation/commencement of treatment and management. Further research with a larger population in different climates is required to explore the status of women with respect to BCRL. The use of common clinical diagnostic criteria did not result in consistent diagnostic classification of BCRL for the women involved in this study.

The reported incidences of breast cancer-related lymphedema (LE) affecting the arms vary greatly. Reason for this variability includes different diagnostic techniques used across studies. In the current study, we compared the accuracy of indocyanine green lymphography (ICG_L) and bioimpedance spectroscopy (BIS) in detecting LE before presentation of clinical signs.

Patients with no initial detectable signs of clinical LE of their arms after axillary lymph node dissection or removal of >5 lymph nodes on sentinel lymph node biopsy were included. Subclinical LE was defined as BIS values outside the normal range [(≥7 units (or >10 units)] or a 7-unit (or 10 unit) change between two measurements. We tracked ICG_L and BIS measurements for 133 potentially affected arms (n = 123). ICG_L detected signs of lymphatic flow disruption in 63 arms (47%). Based on the BIS value of 7 units, 60 arms (45%) had values outside the normal range. When using ICG_L-identified LE cases as true positives, BIS had a 54% accuracy (area under the curve [AUC] = 0.54) in detecting LE. Accuracy was 61% for subclinical LE symptoms when compared with ICG_L (AUC = 0.62). Both BIS and subclinical LE symptoms had <0.70 AUC-receiver characteristic operator curve, suggesting that BIS and development of subclinical LE symptoms are not adequate for identifying patients with subclinical LE.

ICG_L is a reliable diagnostic tool for detecting early signs of lymphatic flow disruption in subclinical LE. Utilizing ICG_L to diagnose subclinical LE followed by a personalized treatment plan may provide patients the best chance of preventing disease progression.

Lymphatic ultrasound has recently been reported useful in the treatment of lymphedema. However, no conclusions have been reached regarding the best probe for lymphatic ultrasound.

This was a retrospective study. Fifteen limbs of 13 patients with lymphedema in whom we could not find dilated lymphatic vessels on lymphatic ultrasound with an 18 MHz probe but later could find them with 33 MHz probe were included. All patients were women, and the mean age was 59.5 years. We performed lymphatic ultrasound in four areas per limb by applying an index of D-CUPS, as we previously reported. We measured the depth and diameter of the lumen of the lymphatic vessels. We also diagnosed the degree of lymphatic degeneration based on the normal, ectasis, contraction, and sclerosis type (NECST) classification.

We found lymphatic vessels in 22/24 (91.7%) areas in the upper limbs and 26/36 (72.2%) areas in the lower limbs. The mean depth and diameter of the lymphatic vessels were 5.2 ± 0.28 mm and 0.33 ± 0.029 mm, respectively. Based on the NECST classification, 68.2% of the upper limbs and 56.0% of the lower limbs were of the ectasis type. We found functional lymphatic vessels in 6/6 (100%) of the upper limbs and 5/7 (71.4%) of the lower limbs, which indicated lymphaticovenous anastomosis (LVA) in these 11 patients.

Using 33 MHz probe, we could detect functional lymphatic vessels in most patients. Even if lymphatic vessels were not found with the 18 MHz probe, LVA could be performed using a higher frequency probe.

: Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model.

: Male C57BL/6N mice (8–10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor receptor-3 (VEGFR-3), vascular endothelial growth factor-C (VEGF-C), and Prospero homeobox 1 (Prox1) on postoperative day 4 was significantly higher in the roxadustat group compared with the control group.

: Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.

Measurements of local tissue water and circumferences are methods to evaluate lymphedema. Knowledge about reference values and reproducibility needs, however, to be determined for the head and neck (HN) area of healthy persons before it can be used in persons with HN lymphedema. The objective of this study was to evaluate the test–retest reliability including measurement errors of local tissue water and neck circumference measurements (CM) in the HN area in a healthy cohort.

Thirty-one women and 29 men were measured on 2 occasions, 14 days apart. The percentage of tissue water content (PWC) were calculated in four facial points and neck CM at three levels. Intraclass correlation coefficient (ICC), changes in mean, standard error of measurement (SEM%), and smallest real difference (SRD%) were calculated. Reliability for PWC was fair to excellent for both women (ICC 0.67–0.89) and men (ICC 0.71–0.87). Measurement errors were acceptable in all points in both women (SEM% 3.6%–6.4%, SRD% 9.9%–17.7%) and men (SEM% 5.1%–10.9%, SRD% 14.2%–30.3%). For the CM, ICCs were excellent both for women (ICC 0.85–0.90) and men (ICC 0.92–0.94), and measurement errors were low (SEM% for women 1.9%–2.1%, SRD% 5.1%–5.9%; SEM% for men 1.6%–2.0%, SRD% 4.6%–5.6%). Most of the lowest values were found close to bone and vessels.

Measurements for PWC and CM in the HN area are reliable in healthy women and men, with acceptable to low measurement errors. PWC points close to bony structures and vessels should, however, be used with caution.

Collecting lymphatic vessel (CLV) dysfunction has been implicated in various diseases, including rheumatoid arthritis (RA). RA patients with active hand arthritis exhibit significantly reduced lymphatic clearance of the web spaces adjacent to the metacarpophalangeal (MCP) joints and a reduction in total and basilic-associated CLVs on the dorsal surface of the hand by near-infrared (NIR) imaging of indocyanine green (ICG). In this pilot study, we assessed direct lymphatic drainage from MCP joints and aimed to visualize the total lymphatic anatomy using novel dual-agent relaxation contrast magnetic resonance lymphography (DARC-MRL) in the upper extremity of healthy human subjects.

Two healthy male subjects >18 years old participated in the study. We performed NIR imaging along with conventional- or DARC-MRL following intradermal web space and intra-articular MCP joint injections. ICG (NIR) or gadolinium (Gd) (MRL) was administered to visualize the CLV anatomy of the upper extremity. Web space draining CLVs were associated with the cephalic side of the antecubital fossa, while MCP draining CLVs were localized to the basilic side of the forearm by near-infrared indocyanine green imaging. The DARC-MRL methods used in this study did not adequately nullify the contrast in the blood vessels, and limited Gd-filled CLVs were identified.

MCP joints predominantly drain into basilic CLVs in the forearm, which may explain the reduction in basilic-associated CLVs in the hands of RA patients. Current DARC-MRL techniques show limited identification of healthy lymphatic structures, and further refinement in this technique is necessary. Clinical trial registration number: NCT04046146.

Indocyanine green (ICG) fluorescence lymphography is widely used to diagnose lymphedema. There is little consensus on the appropriate injection method for ICG fluorescence lymphangiography. We used a three-microneedle device (TMD) for skin injection of ICG solution and investigated its usefulness.

Thirty healthy volunteers were injected with ICG solution using a 27-gauge (27G) needle in one foot and a TMD in the other foot. Injection-related pain was evaluated using the Numerical Rating Scale (NRS) and Face Rating Scale (FRS). The skin depth of the injected ICG solution was evaluated by injecting the solution into the skin of amputated lower limbs using a 27G needle or TMD using ICG fluorescence microscopy. The median and interquartile range of the NRS scores was 3 (3–4) and 2 (2–4) in the 27G needle and TMD groups, respectively; that of the FRS scores was 2 (2–3) and 2 (1–2) in the 27G needle and TMD groups, respectively. Injection-related pain was significantly lower with the TMD than with the 27G needle. The lymphatic vessels were similarly visible using both needles. The depth of the ICG solution varied for each injection with a 27G needle (400–1200 μm) and was consistent at ∼300–700 μm below the skin surface using the TMD. Injection depth was significantly different between the 27G needle and the TMD.

Injection-related pain decreased using the TMD, and ICG solution depth was consistent on fluorescence lymphography. A TMD may be useful for ICG fluorescence lymphography.

Clinical Trials Registry (UMIN-CTR; ID: UMIN000033425).

YouTube provides information on several health-conditions including lipedema. The aim of this study was to investigate the properties, quality, and quantity of YouTube videos on lipedema.

We explored YouTube using the key word lipedema and the initial top 50 videos were included to review. The properties comprising informers, target, and domains of videos covering number of views, likes, dislikes, duration, viewing rate (VR), and video power index (VPI) were recorded. A modified DISCERN tool and global quality scale (GQS) were used to assess the reliability and quality of videos, respectively.

The top 50 videos had a mean of 35,805 views, 282 likes, 12 dislikes, and 30 comments. The mean VPI (96.4) and VR (63.8%) were high. The videos were generally uploaded by health professionals for patient/public and health professional targets with the same ratio (50%). The majority of video contents was related to general information (68%) followed by surgical treatment (62%). Only a small ratio of their content (22%) was about nonsurgical management. The reliability and quality of the videos were intermediate to low. The median DISCERN and GQS scores were higher in the videos uploaded by health professional group compared with nonhealth professionals, but the number of views, VPI, and VR were similar between the groups with regard to the source.

YouTube videos on lipedema are mostly provided by health professionals targeting both public/patients and health care providers but the content is limited and the quality and reliability of them were low to intermediate. Therefore, the lipedema specialists are suggested to work together to create up-to-date, high-quality, accessible online educational content to meet the needs of both patients/public and the health professionals. In addition, control mechanisms and careful peer reviewing of the videos informed by nonhealth professionals are warranted to avoid misleading information.