Analysis on efficacy of magnetic resonance lymphangiography using INV-001 in healthy beagle dogs.

We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

Surgical Treatment of Breast Lymphedema: A Distinct Pathology With Unique Challenges.

BACKGROUND: Supermicrosurgical advances such as lymphovenous bypass (LVB) have enabled effective physiologic treatment of lymphedema affecting the extremities. Reports of surgical treatment for breast lymphedema (BL) are sparse, consisting of case reports and almost exclusively LVB. We report our experience with BL, including a case of mastectomy and breast reconstruction with abdominal free flap and inguinal vascularized lymph node transfer (VLNT) for BL. We compare our series with the surgical literature to discern unique characteristics and treatment limitations inherent to this disease. METHODS: A database was prospectively maintained from September 2020 to May 2023 including all patients diagnosed with BL who were referred to our institution. Breast lymphedema was diagnosed using clinical criteria, and relevant patient data were recorded. Patients interested in surgical management underwent indocyanine green lymphography to determine candidacy for LVB or other interventions. All patients, including those surgically managed, were treated with complex decongestive therapy. RESULTS: Nine patients with BL were included. Eight had undergone breast-conserving therapy for breast cancer with whole breast irradiation. One patient was treated for Hodgkin lymphoma with axillary lymphadenectomy and axillary radiation. Indocyanine green lymphography was performed in 6 patients, of which 4 patients had diffuse dermal backflow. Two patients had lymphatic targets suitable for LVB, including the patient without breast irradiation. Three patients were managed surgically. One patient without bypass targets underwent breast reduction with partial symptomatic relief, later followed by a mastectomy with abdominal free flap reconstruction and VLNT. Two patients with suitable bypass targets underwent LVB, with resolution of breast swelling and subjective symptoms. CONCLUSIONS: The diffuse lymphatic obliteration due to radiation field effect in BL results in a distinct pathophysiology compared with extremity lymphedema. Although published reports of surgical BL treatment almost exclusively describe LVB, other surgical options may be more frequently required. Ablative strategies such as mastectomy and regenerative techniques such as VLNT should be considered potential first-line treatment options for these patients.

Sensitivity of Each Index of Doppler, Cross, Uncollapsible, Parallel, and Superficial Fascia in Lymphatic Ultrasound.

Background: Recently, the usefulness of lymphatic ultrasound has been reported. It is beneficial not only to identify lymphatic vessels but also to evaluate lymphatic degeneration and diagnose lymphedema. We previously proposed D-CUPS (Doppler, Cross, Uncollapsible, Parallel, and Superficial fascia) to identify the lymphatic vessels on ultrasound. The purpose of this study was to clarify the sensitivity of each index of D-CUPS. Methods: We performed a retrospective study of 27 patients (44 limbs, 98 sites) with lower extremity lymphedema, who underwent lymphaticovenous anastomosis (LVA). We performed a lymphatic ultrasound the day before surgery. We used a linear probe commonly used for venous ultrasound (Noblus EUP-L65; Hitachi Medical Corp., Tokyo, Japan). We applied the D-CUPS index to identify the lymphatic vessels on ultrasound. We checked whether lymphatic vessels consistent with preoperative lymphatic ultrasound findings were observed during the LVA. We also calculated the sensitivity of each D-CUPS index. Results: All the 27 patients were women, with a mean age of 59.7 years. Totally, 98 incisions were made (59 incisions on the thigh and 39 incisions on the lower leg). During LVA, lymphatic vessels consistent with the preoperative lymphatic ultrasound findings were observed at all the sites. The sensitivities of each indicator of D-CUPS were 100.0%, 100.0%, 68.4%, 19.4%, and 100.0%, respectively. Conclusion: The sensitivity was 100.0% in D, C, and S. Although each index separately was not perfect, by combining them appropriately, we were able to identify lymphatic vessels with certainty.

Comparing the Impact of Diluents and Injection Techniques on Patient Comfort During Indocyanine Green Lymphangiography: A Prospective Study.

Background: Indocyanine green (ICG) lymphography, a key diagnostic tool for lymphedema, is influenced by the dilution process of ICG dye, impacting patient experience. Methods and Results: In our study, we assessed three different ICG diluents-water for injection (WFI), normal saline (NS), and Dextrose® plus human albumin-in five healthy volunteer individuals undergoing superficial lymphography of the upper limb over 3 weeks. Results indicated that NS, as a diluent for ICG, caused the least discomfort during injection, in contrast to WFI, which led to the highest levels of discomfort. Transport time of ICG from the injection site to the axillary lymph nodes was notably shorter in intradermal injections than in subdermal injections. Conclusion: Our findings advocate for using NS as the optimal and cost-effective diluent for ICG, enhancing patient experience.

Deep learning-based label-free imaging of lymphatics and aqueous veins in the eye using optical coherence tomography.

We demonstrate an adaptation of deep learning for label-free imaging of the micro-scale lymphatic vessels and aqueous veins in the eye using optical coherence tomography (OCT). The proposed deep learning-based OCT lymphangiography (DL-OCTL) method was trained, validated and tested, using OCT scans (23 volumetric scans comprising 19,736 B-scans) from 11 fresh ex vivo porcine eyes with the corresponding vessel labels generated by a conventional OCT lymphangiography (OCTL) method based on thresholding with attenuation compensation. Compared to conventional OCTL, the DL-OCTL method demonstrates comparable results for imaging lymphatics and aqueous veins in the eye, with an Intersection over Union value of 0.79 ± 0.071 (mean ± standard deviation). In addition, DL-OCTL mitigates the imaging artifacts in conventional OCTL where the OCT signal modelling was corrupted by the tissue heterogeneity, provides ~ 10 times faster processing based on a rough comparison and does not require OCT-related knowledge for correct implementation as in conventional OCTL. With these favorable features, DL-OCTL promises to improve the practicality of OCTL for label-free imaging of lymphatics and aqueous veins for preclinical and clinical imaging applications.

Superior lymph node harvest by fluorescent lymphography during minimally invasive gastrectomy for gastric cancer patients with high body mass index.

BACKGROUND: Fluorescent lymphography (FL) using indocyanine green (ICG) allows for the visualization of all draining lymph nodes (LNs), thereby increasing LN retrieval. However, no studies have assessed the efficacy of FL in high body mass index (BMI) gastric cancer patients, even as LN yield decreases with increasing BMI in gastrectomy. This study aimed to investigate the influence of FL on LN retrieval in high BMI gastric cancer patients. METHODS: Gastric cancer patients who underwent laparoscopic or robotic gastrectomies from 2013 to 2021 were included. Patients were classified into two groups, with FL (FL group) or without FL (non-FL group). The effect of FL on LN retrieval was assessed by BMI. Inverse probability of treatment weighting (IPTW) was used to ensure comparability between groups. RESULTS: Retrieved LN number decreased as BMI increased regardless of FL application (P < 0.001). According to the IPTW analysis, the mean retrieved LN number was significantly higher in the FL group (48.4 ± 18.5) than in the non-FL group (39.8 ± 16.3, P < 0.001), irrespective of BMI. The FL group exhibited a significantly higher proportion of patients with 16 or more LNs (99.5%) than the non-FL group (98.1%, P < 0.001). The FL group also had a significantly higher proportion of patients with 30 or more LNs (86.6%) than the non-FL group (72.2%, P < 0.001). In both the normal and high-BMI patients, the FL group had a significantly larger percentage of patients with a higher nodal classification than the non-FL group. CONCLUSION: FL resulted in more LN retrieval, even in high BMI patients. FL ensures accurate staging by maintaining the appropriate retrieved LN number in high BMI gastric cancer patients.

CT features of cutaneous and subcutaneous canine mast cell tumors and utility of conventional and indirect lymphography to detect clinically unknown mast cell tumors and to map the sentinel lymph nodes.

Computed tomography is frequently used to stage canine mast cell tumors (MCTs). The aims of this prospective, observational study were to describe the CT features of MCTs, to evaluate the performance of CT in detecting additional or incidental MCTs, to distinguish between cutaneous (cMCT) or subcutaneous (scMCT) MCTs, and to identify one or multiple sentinel lymph nodes (SLNs) by indirect CT lymphography (ICTL). Seventy-two dogs affected by 111 MCTs were included. The recorded parameters were: shape, size, attenuation (Hounsfield units [HU]), location (cutaneous or subcutaneous), and presence of fat stranding. The SLNs were compared with the regional lymph nodes and supplementary MCTs were registered. Mast cell tumors mostly appeared with well-defined margins (89%), round/oval shape (71%), homogeneous enhancement (90%) with a mean postcontrast density of 62.0 ± 23.4 HU and associated with fat stranding (43%). Cutaneous mast cell tumors were more frequently round (P = .003), whereas scMCTs were oval (P = .011) with a larger mean maximal diameter (2.91 ± 1.57 cm vs 1.46 ± 1.28 cm, P = .002) and more feeding vessels (77% vs 39% P = .044). Compared with histopathology, CT accuracy in differentiating cMCTs and sMCTs was 57%, with an interobserver agreement of 88% (three reviewers). Indirect CT lymphography showed the SLN in 82 of 85 (97%) cases, 32% of them not corresponding to the regional node. CT showed additional or incidental MCTs in 23 of 72 (32%) dogs. In conclusion, the common CT appearance of canine cMCTs and scMCTs is reported with some statistical differences between the two categories. CT is useful in identifying clinically undetected MCTs and SLNs, although it shows low accuracy in distinguishing between cMCT and scMCT.

Treatment Of Post-Operative Chylothorax: The Role Of Intranodal Lymphangiography And Thoracic Duct Disruption.

Thoracic duct embolization has been increasingly adopted as a first-line therapy of chylothorax and this procedure includes lipiodol lymphangiography, thoracic duct access and embolization. Lymphangiography itself has a therapeutic role, with volume-dependent success rates of 37%-97% and even a reported 100% success rate in outputs of < 500 mL/day. We present a clinical case of a 48-years-old man diagnosed with esophageal squamous cell carcinoma, who underwent esophagectomy and presented with post-operative high-output (> 1L/day) chylothorax; thoracic duct embolization was proposed. Even though thoracic duct access and embolization were not achieved due to technical and anatomical factors, lipiodol lymphangiography and possibly thoracic duct maceration (after several punctures/attempts) contributed to the clinical success of the procedure, and this chylothorax with output values superior to those reported in the literature resolved within three days. As such, the therapeutic role of intranodal lymphangiography and thoracic duct disruption should be taken into account.

[Fluorescence lymphography for sentinal lymph node biopsy in breast cancer]. / Sobstvennyi opyt primeneniya flyuorestsentnoi limfografii dlya biopsii signal'nykh limfouzlov pri rake molochnoi zhelezy.

OBJECTIVE: To study diagnostic value of fluorescence lymphography for sentinel lymph node biopsy in breast cancer. MATERIAL AND METHODS: The study enrolled 25 patients with breast cancer T1-2N0-1M0 between March 2023 and July 2023. Eight ones underwent neoadjuvant chemotherapy. In 3 patients, morphologically verified metastases cN1 in axillary lymph nodes regressed after treatment. After sentinel lymph node biopsy, all patients underwent standard axillary lymphadenectomy. Subareolar injection of indocyanine green 1 ml (5 mg/ml) was performed immediately before surgery. Fluorescence imaging was performed using the MARS system. RESULTS: Detection rate was 100%. Mean number of sentinel lymph nodes was 2. Metastatic lesions of sentinel lymph nodes were observed in 6 patients (24%) with micro-metastases in 2 cases. In 50% of cases, metastatic lesion did not extend beyond sentinel lymph nodes. False negative result was obtained in 1 (4%) patient. Mean number of metastases was 1.8 (max 3 in one patient). CONCLUSION: Sentinel lymph node biopsy with fluorescence lymphography is a sensitive method. The advantages of this technique are visualization of subcutaneous lymphatic vessels and skin incision for access to sentinel lymph nodes, as well as visualization of sentinel lymph nodes after skin incision.

Preoperative photoacoustic versus indocyanine green lymphography in lymphaticovenular anastomosis outcomes for lower extremity lymphedema: A pilot study.

BACKGROUND: Identification of the proper lymphatics is important for successful lymphaticovenular anastomosis (LVA) for lymphedema; however, visualization of lymphatic vessels is challenging. Photoacoustic lymphangiography (PAL) can help visualize lymphatics more clearly than other modalities. Therefore, we investigated the usefulness of PAL and determined whether the clear and three-dimensional image of PAL affects LVA outcomes. METHODS: We recruited 22 female patients with lower extremity lymphedema. The operative time, number of incisions, number of anastomoses, lymphatic vessel detection rate (number of functional lymphatics identified during the operation/number of incisions), and limb volume changes preoperatively and 3 months postoperatively were compared retrospectively. The patients were divided according to whether PAL was performed or not, and results were compared between those undergoing PAL (PAL group; n = 10) and those who did not (near-infrared fluorescence [NIRF] group, n = 12). RESULTS: The mean age of the patients was 55.9 ± 15.1 years in the PAL group and 50.7 ± 14.9 years in the NIRF group. One patient in the PAL group and three in the NIRF group had primary lymphedema. Eighteen patients (PAL group, nine; and NIRF group, nine) had secondary lymphedema. Based on preoperative evaluation using the International Society of Lymphology (ISL) classification, eight patients were determined to be in stage 2 and two patients in late stage 2 in the PAL group. In contrast, in the NIRF group, one patient was determined to be in stage 0, three patients each in stage 1 and stage 2, and five patients in late stage 2. Lymphatic vessel detection rates were 93% (42 LVAs and 45 incisions) and 83% (50 LVAs and 60 incisions) in the groups with and without PAL, respectively (p = 0.42). Limb volume change was evaluated in five limbs of four patients and in seven limbs of five patients in the PAL and NIRF groups as 336.6 ± 203.6 mL (5.90% ± 3.27%) and 52.9 ± 260.7 mL (0.71% ± 4.27%), respectively. The PAL group showed a significant volume reduction. (p = .038). CONCLUSIONS: Detection of functional lymphatic vessels on PAL is useful for treating LVA.

Advances in lymphedema: An under-recognized disease with a hopeful future for patients.

Lymphedema has traditionally been underappreciated by the healthcare community. Understanding of the underlying pathophysiology and treatments beyond compression have been limited until recently. Increased investigation has demonstrated the key role of inflammation and resultant fibrosis and adipose deposition leading to the clinical sequelae and associated reduction in quality of life with lymphedema. New imaging techniques including magnetic resonance imaging (MRI), indocyanine green lymphography, and high-frequency ultrasound offer improved resolution and understanding of lymphatic anatomy and flow. Nonsurgical therapy with compression, exercise, and weight loss remains the mainstay of therapy, but growing surgical options show promise. Physiologic procedures (lymphovenous anastomosis and vascularized lymph node transfers) improve lymphatic flow in the diseased limb and may reduce edema and the burden of compression. Debulking, primarily with liposuction to remove the adipose deposition that has accumulated, results in a dramatic decrease in limb girth in appropriately selected patients. Though early, there are also exciting developments of potential therapeutic targets tackling the underlying drivers of the disease. Multidisciplinary teams have developed to offer the full breadth of evaluation and current management, but the development of a greater understanding and availability of therapies is needed to ensure patients with lymphedema have greater opportunity for optimal care.

Contrast-enhanced ultrasonography as an adjunctive method to ICG lymphography for functional lymphaticovenous anastomosis.

BACKGROUND AND OBJECTIVES: Indocyanine green (ICG) lymphography is the reference standard for evaluating lymphedema stage and identifying lymphatic vessels. However, the penetration depth was limited to 1-2 cm from the skin surface. This prospective study compares clinical outcomes following lymphaticovenous anastomoses (LVA) in patients with upper and lower limb lymphedema using contrast-enhanced ultrasonography (CEUS) with ICG as a preoperative imaging modality. METHODS: Under general anesthesia, Sonazoid® was injected subcutaneously to visualize functional lymphatic channels via CEUS. We analyzed the changes in limb circumference and inter-limb ratio (ILR) using bioimpedance to measure electrical resistance between the CEUS plus ICG group and the ICG-only group to see the effect of CEUS-assisted LVA. RESULTS: No significant demographic differences existed between the two groups (CEUS plus ICG group vs. ICG-only group). The ILR decrease of the Z1 value measured using bioimpedance was statistically significant (p = 0.042 for the upper limb, p = 0.002 for the lower limb)- CONCLUSIONS: CEUS allowed us to identify deep-lying, functional, and large lymphatic channels. In conclusion, the combination of CEUS and ICG for identifying lymphatic channels has the potential to lead to a more functional lymphovenous anastomosis.

Pulmonary interstitial lymphography: A prospective trial with potential impact on stereotactic ablative radiotherapy planning for early-stage lung cancer.

This prospective feasibility trial investigated pulmonary interstitial lymphography to identify thoracic primary nodal drainage (PND). A post-hoc analysis of nodal recurrences was compared with PND for patients with early-stage lung cancer; larger studies are needed to establish correlation. Exploratory PND-inclusive stereotactic ablative radiotherapy plans were assessed for dosimetric feasibility.

Three-dimensional non-contrast magnetic resonance lymphography severity stage for upper extremity lymphedema.

PURPOSES: Non-contrast magnetic resonance lymphography (NMRL) has recently shown the capability of evaluating anatomical fluid distribution in upper extremity lymphedema (UEL). However, there is still a lack of knowledge about the correlation between the characteristic three-dimensional (3D) NMRL findings and the indocyanine green lymphography (ICG-L) findings. Our goal was to clarify the relationship between the 3D NMRL findings and the ICG-L findings. METHODS: Medical charts of patients with secondary UEL who underwent NMRL and ICG-L between January 2018 to October 2021 were reviewed. The upper extremities were divided into 6 regions; the hand, elbow, and the radial and ulnar aspects of the forearm and the upper arm. We investigated the prevalence of characteristic 3D NMRL patterns (Mist/Spray/Inky) in each region based on the ICG-L stage. We also examined the association between the 3D NMRL stage which we proposed and the ICG-L stage, and other clinical factors. RESULTS: A total of 150 regions of 25 patients with upper extremities lymphedema were enrolled in the study. All of the characteristic patterns increased significantly as the ICG-L stage advanced (p < 0.001, < 0.001, and < 0.001, respectively). The predominant NMRL patterns changed significantly from the Early pattern (Mist pattern) to the Advanced pattern (Inky/Spray pattern) as the ICG-L stage progressed (p < 0.001). The higher Stage of 3D NMRL was significantly associated with the progression of the ICG-L stage (rs = 0.80, p < 0.001). CONCLUSIONS: Characteristic 3D NMRL patterns and the 3D NMRL Stage had a significant relationship with the ICG-L stage and other clinical parameters. This information may be an efficient tool for a more precise and objective evaluation of various treatments for UEL patients.

MR Lymphangiography in Lymphatic Disorders: Clinical Applications, Institutional Experience, and Practice Development.

Lymphatic flow and anatomy can be challenging to study, owing to variable lymphatic anatomy in patients with diverse primary or secondary lymphatic pathologic conditions and the fact that lymphatic imaging is rarely performed in healthy individuals. The primary components of the lymphatic system outside the head and neck are the peripheral, retroperitoneal, mesenteric, hepatic, and pulmonary lymphatic systems and the thoracic duct. Multiple techniques have been developed for imaging components of the lymphatic system over the past century, with trade-offs in spatial, temporal, and contrast resolution; invasiveness; exposure to ionizing radiation; and the ability to obtain information on dynamic lymphatic flow. More recently, dynamic contrast-enhanced (DCE) MR lymphangiography (MRL) has emerged as a valuable tool for imaging both lymphatic flow and anatomy in a variety of congenital and acquired primary or secondary lymphatic disorders. The authors provide a brief overview of lymphatic physiology, anatomy, and imaging techniques. Next, an overview of DCE MRL and the development of an MRL practice and workflow in a hybrid interventional MRI suite incorporating cart-based in-room US is provided, with an emphasis on multidisciplinary collaboration. The spectrum of congenital and acquired lymphatic disorders encountered early in an MRL practice is provided, with emphasis on the diversity of imaging findings and how DCE MRL can aid in diagnosis and treatment of these patients. Methods such as DCE MRL for assessing the hepatic and mesenteric lymphatic systems and emerging technologies that may further expand DCE MRL use such as three-dimensional printing are introduced. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Association between Bioimpedance Spectroscopy and Magnetic Resonance Lymphangiography in the Diagnosis and Assessment of Lymphedema.

BACKGROUND: This study assesses associations between bioimpedance spectroscopy (BIS) and magnetic resonance lymphangiography (MRL) in the staging and assessment of lymphedema. METHODS: Adults who received MRL and BIS between 2020 and 2022 were included. We collected fluid, fat, and lymphedema severity ratings, and measured fluid stripe thickness, subcutaneous fat width, and lymphatic diameter on MRL. BIS lymphedema index (L-Dex) scores were collected from patient charts. We assessed sensitivity and specificity of L-Dex scores to detect MRL-identified lymphedema, and examined associations between L-Dex scores and MRL imaging measures. RESULTS: Forty-eight limbs across 40 patients were included. L-Dex scores had 72.5% sensitivity and 87.5% specificity for detecting MRL-defined lymphedema, with a 96.7% estimated positive predictive value and 38.9% negative predictive value. L-Dex scores were associated with MRL fluid and fat content scores (p ≤ 0.05), and lymphedema severity (p = 0.01), with better discrimination between fluid than fat content levels on pairwise analysis, and poor discrimination between adjacent severity levels. L-Dex scores were correlated with distal and proximal limb fluid stripe thickness (distal: rho = 0.57, p < 0.01; proximal: rho = 0.58, p < 0.01), partially correlated with distal subcutaneous fat thickness when accounting for body mass index (rho = 0.34, p = 0.02), and were not correlated with lymphatic diameter (p = 0.25). CONCLUSION: L-Dex scores have high sensitivity, specificity, and positive predictive value for the identification of MRL-detected lymphedema. L-Dex has difficulty distinguishing between adjacent severity levels of lymphedema and a high false negative rate, explained in part by reduced discrimination between levels of fat accumulation.

Patient characteristics may affect the lymphatic staining ability of Indocyanine green and Patent blue during lymphaticovenous anastomosis.

BACKGROUND: The use of dyes like Indocyanine green (ICG) and Patent blue facilitates the identification of lymphatic vessels during lymphaticovenous anastomosis (LVA) surgery. However, some patients experience "staining failure". In these cases, no stained lymphatic vessels can be detected, making supermicrosurgical LVA even more complex. OBJECTIVE: This study aims to investigate patient-related factors that may interfere with lymphatic vessel staining during LVA. METHODS: A retrospective study was conducted on 30 patient charts, focusing on patient characteristics and the staining quality of ICG and Patent blue dye. Statistical analyses were performed to identify correlations between variables. RESULTS: Significant correlations were found between higher age and secondary lymphedema, longer duration of lymphedema in male patients until surgery and reoccurring cellulitis and Patent blue staining. Notably, recurrent infections to the lymphatic system resulted in inferior staining ability during LVA surgery. CONCLUSIONS: Due to staining failure the detection of functional lymphatic vessels remains challenging in LVA surgery. A more extensive preoperative workup is recommended for patients with recurrent cellulitis to optimize surgical feasibility and procedure quality in LVA treatment for lymphedema.