Publications

Chronic lymphedema is a progressive, disfiguring disease that results from dysfunction of the lymphatic vasculature, causing distal accumulation of interstitial fluid, localized development of tissue edema, and expansion of subcutaneous adipose tissue (SAT). As the molecular mechanisms governing SAT remodeling in this disease are unclear, we performed single-nucleus RNA sequencing on paired control and affected SAT biopsies from patients with unilateral lymphedema. Lymphedema samples were characterized by expansion of SAA + adipocytes, pro-adipogenic stem cells, and proliferation of lymphatic capillaries. A GRIA1 + lymphedema-enriched stromal cell population expressing VEGFC , ADAMTS3 , and CCBE1 was identified, suggesting an enhanced axis of communication between adipose stem and progenitor cells (ASPCs) and lymphatic endothelial cells. Furthermore, lymphedema ASPC-conditioned media promoted lymphatic endothelial tube elongation in vitro . These findings indicate a critical role for ASPCs in regulating adipocyte differentiation and lymphatic vascular remodeling in lymphedema, and provide a valuable resource for better understanding this disease.

BACKGROUND: Lymphedema is a prevalent and underserved condition. Expanding diagnostic and therapeutic options have increased interest in multidisciplinary care. This study examines clinical characteristics and geographic patterns of lymphedema care within a multidisciplinary lymphatic center.

METHODS: A retrospective review included all patients evaluated for edema at the BIDMC Lymphatic Center from January 2018 through December 2023. The multidisciplinary team comprised cardiovascular medicine, radiology, plastic surgery, and physical therapy. A RedCap registry captured demographics, clinical characteristics, imaging and surgeries. Patients were stratified by etiology as primary, secondary, or non-lymphatic edema. Bivariate and geospatial analyses assessed differences across groups and geographic access to care.

RESULTS: Of the total 2,031 participants, 76% were female, with a mean age of 60 years (±15.2) and BMI of 33.6 kg/m2 (±10.7). The average duration of edema symptoms at evaluation was 9.47 years (±11.8). Secondary lymphedema was most common (n=1,104, 54%), often due to cancer (54%) or chronic venous disease (23%). Lymphatic imaging was performed in 549 patients (27%). Of those 549, lymphoscintigraphy (83%) and MRI (69%) were most common. Only 149 patients (11%) underwent surgery. Patients residing outside the state had longer symptom duration (12.3 vs 9.1 years, p<0.0001) and higher surgical rates (16.6% vs 6%, p<0.001) than those residing in-state.

CONCLUSIONS: In this large, single-center description, over one-third of patients did not have lymphedema. Lymphatic imaging was frequently performed, though few underwent surgery. Geographic barriers delayed evaluation and increased surgical intervention, emphasizing the need for broader access to multidisciplinary lymphatic care.

The sixth most common cancer in developing countries is the esophageal squamous cell carcinoma (ESCC), with a poor prognosis because the 5-year survival rate of patients with ESCC is only 35%. The incidence of ESCC is influenced by various factors, including diet, genetics, environmental exposures, and socio-economic status; almost all biological drivers of ESCC involve cancer stem cells (CSCs), which drive tumor initiation, therapy resistance, recurrence, and metastasis. CSC-related biomarkers in ESCC provide useful information on prognosis, diagnosis, and treatment methods. The accessory characteristics that identify CSCs are unique enzymatic activity, surface markers, and drug resistance; hence, contributing to their ability to overcome traditional forms of chemotherapy and radiotherapy. These biomarkers not only enable the isolation of CSCs but are also highly correlated with the clinical outcome of ESCC. A multiconjugation of certain CSC markers can improve detection accuracy and inform more precise treatment strategies. In addition, the development of ESCC-specific CSC biomarkers has the potential to develop targeted immunotherapy, which will eventually result in better patient outcomes. A CSC-based therapeutic approach provides a holistic understanding of CSC biology and the development of comprehensive treatment options for ESCC. Although several studies have investigated CSCs across various contexts, a comprehensive review focusing on their role, biomarkers, and therapeutic potential in ESCC is currently lacking, and this review aims to address that gap.

PURPOSE: Regional nodal irradiation (RNI) increases breast cancer-related lymphedema (BCRL) following axillary lymph node dissection despite immediate lymphatic reconstruction (ILR). This study examines the relationship between radiation (RT) dose to the ILR anastomosis and BCRL.

METHODS AND MATERIALS: This prospective study included 23 patients with invasive breast cancer who underwent axillary lymph node dissection/ILR followed by RNI. The anastomosis was indicated by a twirl clip, allowing for ILR contouring. The median RNI dose was 4000 cGy in 16 fractions. Lymphedema was defined as an increase in arm volume (10% dominant, 7% nondominant) in the affected extremity or a 10-point increase in Lymphedema Index plus patient-reported symptoms >6 months after RT completion. Dosimetric parameters included mean and maximum doses, V35, V40, Dmin<36.8Gy at the ILR site, ILR + 5 mm, and ILR + 2 cm expansion volumes.

RESULTS: Median follow-up was 25.9 months (interquartile range, 22.8-33.9). Fourteen patients met criteria for lymphedema at >1 time point, but only 4 (17.4%) met criteria for BCRL at their last follow-up. Patients who developed lymphedema had higher mean dose (4135 cGy vs 1410 cGy; P = .006), V35 (89% vs 20%; P = .005), and V40 (84% vs 17%; P = .012) at the ILR + 2 cm volume compared with those who did not. These parameters remained significant after controlling for BMI and the number of nodes removed. Threshold doses for lymphedema risk were found for the ILR + 2 cm volume: mean dose, 3074 cGy (AUC = 0.86), with rates of lymphedema above and below the threshold at 92% versus 30%, P = .006; V35, 56% (AUC = 0.87), 92% versus 22%, P = .001; and V40, 50% (AUC = 0.83), 92% versus 30%, P = .006.

CONCLUSIONS: Increasing RT doses to the ILR anastomosis site and the surrounding area increased lymphedema risk. Future studies will assess whether limiting the dose below these thresholds can lower BCRL rates while maintaining disease control.

Immediate lymphatic reconstruction (ILR), originally described as the lymphatic microsurgical preventative healing approach (LYMPHA), reduces the risk of developing lymphedema secondary to breast cancer treatment. ILR involves the intussusception of arm lymphatic channels into a vein draining centrally. However, performing this technique in a deep surgical field is technically challenging. We introduce a technical modification to ILR by repurposing a pulmonary wire to facilitate the intussusception technique. Intraoperatively, fluorescein isothiocyanate (FITC) was injected into the first and forth webspaces on the dorsum of the hand and the volar wrist. A vein graft was harvested from the lower leg during the axillary lymph node dissection. The accessory branch of the axillary vein was isolated. Lymphatic channels were identified under a 560-nm filter in the axillary bed. The largest-diameter channel was selected and isolated. An anastomosis was performed between the vein graft and targeted lymphatic channel utilizing the intussusception technique. A mini-forceps was passed retrograde through the vein graft to grasp the lymphatic channel. The channel was then intussuscepted into the vein graft and released. The vein graft was sutured to the surrounding peri-lymphatic fat using 8-0 sutures. Lymphatic flow from the proximal end of the vein graft was confirmed with FITC imaging. The vein graft was then anastomosed to the accessory vein using a coupler device. Patency was confirmed by visualizing FITC dye crossing the anastomosis and filling the recipient vein. Use of mini-forceps in ILR improves lymphatic channel manipulation in a deep surgical field and eliminates the U-Stitch.

BACKGROUND: Lymphatic anatomy has primarily been described in cadaveric dissections. Mapping of the upper extremity superficial lymphatic system with indocyanine green (ICG) lymphography provides functional insights and detail to major anatomic variations.

METHODS: Healthy female volunteers underwent lymphatic mapping of the upper extremities with ICG lymphography. ICG was injected in six standard sites in the hand/wrist and upper arm. Major anatomic variations of four main forearm pathways and connectivity to four upper arm pathways were described.

RESULTS: 90 arms of 45 volunteers were included. The posterior radial channel predominantly courses in the dorsal forearm (98%). The posterior ulnar forearm pathway courses in the dorsal forearm in the majority of arms (70%). The anterior radial and anterior ulnar forearm channels exclusively course in the volar forearm (100%). The posterior radial pathway connects to the bicipital (80%), lateral (48%), medial (9%), and tricipital (7%) upper am pathways. The posterior ulnar pathway connects to the lateral (54%), tricipital (51%), medial (21%), and bicipital (14%) upper arm pathways. The anterior radial pathway connects to the medial (50%) and bicipital (60%) pathways. The anterior ulnar pathway connects to the medial (54%) and bicipital (59%) pathways.

CONCLUSIONS: Upper extremity lymphatic drainage to the lateral and tricipital pathways is enabled exclusively by the dorsal forearm channels suggesting their importance in BCRL risk. Variations of upper extremity lymphatic anatomy are relevant to the risk, prevention, and treatment of breast cancer-related lymphedema risk and warrant further study.

Despite major advancements in lymphatic care, there remains a lack of consensus across institutions regarding the evaluation and surgical management of lymphedema. The aim of this study is to describe the practices for diagnosis and surgical treatment of lymphedema across accredited Lymphatic Education & Research Network (LE&RN) comprehensive Centers of Excellence (COEs).A survey was distributed to directors of the 16 LE&RN comprehensive COEs in January 2023. Directors were queried on lymphatic surgeon training, evaluation of potential surgical patients, description of surgical operations offered at their center, surgical algorithms, and operative techniques for various procedures.Nine COEs completed the survey (56% response rate). Eight of nine centers reported having an interdisciplinary surgical evaluation program, including lymphatic surgery (100%, 8/8), certified lymphedema therapy (100%, 8/8), and lymphatic medicine (75%, 6/8). COEs use a variety of lymphatic imaging modalities, with indocyanine green lymphography (89%, 8/9) and lymphoscintigraphy (78%, 7/9) being the most common. While all COEs offered debulking procedures, 67% (6/9) offered physiologic procedures (lymphovenous bypass and vascularized lymph node transplant), and 56% (5/9) offered immediate lymphatic reconstruction. There was no consensus on surgical algorithms or operative approaches.LE&RN comprehensive COEs consistently use multidisciplinary care teams for medical and surgical evaluations, but there is significant variability in lymphatic imaging modalities used and lymphatic surgery types and techniques. These findings underscore the need for continued research and standardization of lymphatic surgery outcomes to develop consensus.

OBJECTIVE: To identify vulnerable upper extremity regions in native lymphatic anatomy that predispose women to the development of breast cancer-related lymphedema. Additionally, to identify currently available imaging technologies that could be repurposed for in-vivo lymphatic imaging of these anatomic regions and pathways.

BACKGROUND: Breast cancer-related lymphedema remains an incurable complication of breast cancer treatment, but improvements to knowledge of upper extremity lymphatic anatomy and imaging can unlock new techniques for prevention and treatment.

METHODS: "Bringing to Light the Invisible Lymphatic Anatomy of the Human Body" was a two day accelerator workshop held in May 2024 at the Harvard Radcliffe Institute attended by sixteen experts in lymphatic anatomy and imaging including four lymphatic anatomists, five imaging clinicians, three lymphatic scientists, and three program officers from the National Heart, Lung and Blood Institute (NHLBI) and Advanced Research Projects Agency for Health (ARPA-H).

RESULTS: Collateral pathways of the superficial lymphatic system, perforating lymphatic vessels, and the deep lymphatic system were implicated in preventing or reducing the severity of BCRL. Several strategies were proposed for repurposing existing imaging technology and developing new imaging technology that can improve understanding of the anatomy, function, and connectivity of lymphatic vessels in these three regions of the arm.

CONCLUSION: Advancements in lymphatic imaging are central to refining our knowledge of lymphatic anatomy. Key challenges to lymphatic imaging are visualization of the deep lymphatic system and perforating lymphatic vessels.

BACKGROUND: The lateral upper arm (LUA) pathway is a route of superficial lymphatic drainage that bypasses the axilla by draining to the deltopectoral, clavicular, and cervical lymph nodes. Despite the fact that anatomic variations of the LUA pathway have been implicated in breast cancer-related lymphedema (BCRL) risk after axillary lymph node dissection (ALND), the incidence of the LUA pathway variations in the healthy population has never been reported.

METHODS: Healthy female volunteers underwent bilateral lymphatic mapping of the upper extremities with indocyanine green (ICG) lymphography. ICG was injected in six standard sites in the hand/wrist and upper arm. Major anatomic variations of the LUA pathway were recorded including bundle phenotype (long, short, or absent), proximal visualization sites, and forearm pathway continuation to the long bundle phenotype.

RESULTS: 90 arms of 45 volunteers were included. The LUA pathway was present in 99% of arms and a long-versus-short bundle phenotype was observed in 71% versus 28% of arms. When the long bundle was present, it was formed by continuity with the forearm posterior radial channel alone (47%), posterior ulnar channel alone (34%), or both channels (19%). The LUA pathway was traced proximally to the deltopectoral groove in 89% of arms and to the axilla in 11% of arms.

CONCLUSIONS: We observed similar proportions of arms with long and short bundle phenotypes in comparison to our previous report of the LUA pathway in breast cancer patients with nodal disease. Defining the incidence of the LUA pathway with its variations in the general population is important as variations in this pathway may have implications for an individual's risk of developing BCRL.