Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation.

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.

Mapping the Anatomy of the Human Lymphatic System.

BACKGROUND: While substantial anatomical study has been pursued throughout the human body, anatomical study of the human lymphatic system remains in its infancy. For microsurgeons specializing in lymphatic surgery, a better command of lymphatic anatomy is needed to further our ability to offer surgical interventions with precision. In an effort to facilitate the dissemination and advancement of human lymphatic anatomy knowledge, our teams worked together to create a map. The aim of this paper is to present our experience in mapping the anatomy of the human lymphatic system. METHODS: Three steps were followed to develop a modern map of the human lymphatic system: (1) identifying our source material, which was "Anatomy of the human lymphatic system," published by Rouvière and Tobias (1938), (2) choosing a modern platform, the Miro Mind Map software, to integrate the source material, and (3) transitioning our modern platform into The Human BioMolecular Atlas Program (HuBMAP). RESULTS: The map of lymphatic anatomy based on the Rouvière textbook contained over 900 data points. Specifically, the map contained 404 channels, pathways, or trunks and 309 lymph node groups. Additionally, lymphatic drainage from 165 distinct anatomical regions were identified and integrated into the map. The map is being integrated into HuBMAP by creating a standard data format called an Anatomical Structures, Cell Types, plus Biomarkers table for the lymphatic vasculature, which is currently in the process of construction. CONCLUSION: Through a collaborative effort, we have developed a unified and centralized source for lymphatic anatomy knowledge available to the entire scientific community. We believe this resource will ultimately advance our knowledge of human lymphatic anatomy while simultaneously highlighting gaps for future research. Advancements in lymphatic anatomy knowledge will be critical for lymphatic surgeons to further refine surgical indications and operative approaches.

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.

Expanding Access to Immediate Lymphatic Reconstruction Through an Axillary Surgery Referral Program: A 6-Year Single-Center Experience.

BACKGROUND: Recent advances in breast cancer have progressed toward less aggressive axillary surgery. However, axillary lymph node dissection (ALND) remains necessary in specific cases and can increase the risk of lymphedema. Performing ALND with immediate lymphatic reconstruction (ILR) can help lower this risk. This report outlines the implementation of an Axillary Surgery Referral Program (ASRP) to broaden access to ILR, providing insights for institutions considering similar initiatives. METHODS: A retrospective study analyzed patients referred to the ASRP at Beth Israel Deaconess Medical Center (BIDMC) between 6 January 2017 and 10 December 2022. Patients were identified from a prospective registry, with data subsequently extracted from electronic medical records. This analysis specifically centered on patients referred from external institutions to undergo ALND with ILR. RESULTS: The program received referrals for 131 patients from institutions across five different states. Annual referrals steadily increased over time. The primary indication for referral was residual axillary disease after neoadjuvant chemotherapy (41.2%). Among the referrals, 20 patients (15.3%) no longer required ALND due to axillary pathologic complete response to neoadjuvant therapy. Care coordination played a crucial role in streamlining the patient care process for both efficiency and effectiveness. CONCLUSION: The ASRP expands access to ILR for patients with breast cancer, the majority referred for surgical management of residual disease after chemotherapy. The program provides a model for health care institutions aiming to establish similar specialized referral services. Continued program evaluation will be instrumental in refining axillary surgery referral practices and ensuring optimal patient care.

Evaluation of Primary Lymphedema with Intranodal Lymphangiography.

PURPOSE: There are limited existing data on the lymphatic anatomy of patients with primary lymphedema (LED), which is caused by aberrant development of lymphatic channels. In addition, there is a paucity of contemporary studies that use groin intranodal lymphangiography (IL) to evaluate LED anatomy. The purpose of this retrospective observational study was to better delineate the disease process and anatomy of primary LED using groin IL. MATERIALS AND METHODS: We identified common groin IL findings in a cohort of 17 primary LED patients performed between 1/1/2017 and 1/31/2022 at a single institution. These patients were clinically determined to have primary lymphedema and demonstrated associated findings on lower extremity MR and lymphoscintigraphy. RESULTS: Ten patients (59%) demonstrated irregular lymph node morphology or a paucity of lymph nodes on the more symptomatic laterality. Eight patients (47%) demonstrated lymphovenous shunting from pre-existing anastomoses between the lymphatic and venous systems. Eight patients (47%) demonstrated passage of contrast past midline to the contralateral lymphatics. Finally, 12 patients (71%) failed to opacify the cisterna chyli and thoracic duct on their initial lymphangiograms. Delayed computed tomography of 3 patients showed eventual central lymphatic opacification up to the renal veins, but none of these patients showed central lymphatic opacification to the thorax. CONCLUSION: This descriptive, exploratory study demonstrates common central groin IL findings in primary LED to highlight patterns interventional radiologists should identify and report when addressing primary LED.

Edematous Dermal Thickening on Magnetic Resonance Imaging as a Biomarker for Lymphatic Surgical Outcomes.

Background and Objectives: One of the surgical treatments for breast cancer-related lymphedema (BCRL) is debulking lipectomy. The aim of this study is to investigate whether dermal thickness could be utilized as an objective indicator of post-operative changes following debulking. Materials and Methods: A retrospective review of BCRL patients who underwent debulking lipectomy was conducted. MRI-based dermal thickness was measured by two separate trained readers at 16 regions of the upper extremity. Pre- and post-operative reduction in dermal thickness was compared across the affected and unaffected (control) arms for each patient. The Wilcoxon rank sum test was used to assess for significant change. Univariate linear regression was used to assess the relationship between dermal thickness reduction and changes to LYMPH-Q scores, L-Dex scores, and relative volume change. Results: Seventeen patients were included in our analysis. There was significant reduction in dermal thickness at 5/16 regions in the affected arm. Dermal thickness change was significantly correlated with LYMPH-Q scores, L-Dex scores, and relative volume change in 2/16 limb compartments. There was predominant dermal thickening in the dorsal compartment of the upper arm and in the ventral and ulnar compartments of the forearm. Conclusions: Dermal thickness shows promising utility in tracking post-operative debulking procedures for breast cancer-related lymphedema. Further studies with larger patient populations and a variety of imaging modalities are required to continue to develop a clinically objective and reproducible method of post-surgical lymphedema staging and monitoring.

Fluid Distribution Patterns in Early-Stage Upper Extremity Lymphedema.

INTRODUCTION: Magnetic resonance imaging (MRI) stage 1 (early stage) upper extremity lymphedema is characterized by fluid infiltration in the subcutaneous tissues that does not exceed 50% of the extremity circumference at any level. The spatial fluid distribution in these cases has not been detailed and may be important to help determine the presence and location of compensatory lymphatic channels. The aim of this study is to determine whether there was a pattern of distribution of fluid infiltration in patients with early-stage lymphedema that could correspond to known lymphatic pathways in the upper extremity. METHODS: A retrospective review identified all patients with MRI stage 1 upper extremity lymphedema who were evaluated at a single lymphatic center. Using a standardized scoring system, a radiologist graded the severity of fluid infiltration at 18 anatomical locations. A cumulative spatial histogram was then created to map out regions where fluid accumulation occurred most and least frequently. RESULTS: Eleven patients with MRI stage 1 upper extremity lymphedema were identified between January 2017 and January 2022. The mean age was 58 years and the mean BMI was 30 m/kg2. One patient had primary lymphedema and the remaining 10 had secondary lymphedema. The forearm was affected in nine cases, and fluid infiltration was predominantly concentrated along the ulnar aspect, followed by the volar aspect, while the radial aspect was completely spared. Within the upper arm, fluid was primarily concentrated distally and posteriorly, and occasionally medially. CONCLUSIONS: In patients with early-stage lymphedema, fluid infiltration is concentrated along the ulnar forearm and the posterior distal upper arm, which aligns with the tricipital lymphatic pathway. There is also sparing of fluid accumulation along the radial forearm in these patients, suggesting a more robust lymphatic drainage along this region, possibly due to a connection to the lateral upper arm pathway.

Non-Linear Lymphatic Anatomy in Breast Cancer Patients Prior to Axillary Lymph Node Dissection: A Risk Factor For Lymphedema Development.

Immediate lymphatic reconstruction (ILR) at the time of axillary lymph node dissection (ALND) has become increasingly utilized for the prevention of breast cancer related lymphedema. Preoperative indocyanine green (ICG) lymphography is routinely performed prior to an ILR procedure to characterize baseline lymphatic anatomy of the upper extremity. While most patients have linear lymphatic channels visualized on ICG, representing a non-diseased state, some patients demonstrate non-linear patterns. This study aims to determine potential inciting factors that help explain why some patients have non-linear patterns, and what these patterns represent regarding the relative risk of developing postoperative breast cancer related lymphedema in this population. A retrospective review was conducted to identify breast cancer patients who underwent successful ILR with preoperative ICG at our institution from November 2017-June 2022. Among the 248 patients who were identified, 13 (5%) had preoperative non-linear lymphatic anatomy. A history of trauma or surgery of the affected limb and an increasing number of sentinel lymph nodes removed prior to ALND appeared to be risk factors for non-linear lymphatic anatomy. Furthermore, non-linear anatomy in the limb of interest was associated with an increased risk of postoperative lymphedema development. Overall, non-linear lymphatic anatomy on pre-operative ICG lymphography appears to be a risk factor for developing ipsilateral breast cancer-related lymphedema. Guided by the study's findings, when breast cancer patients present with baseline non-linear lymphatic anatomy, our institution has implemented a protocol of prophylactically prescribing compression sleeves immediately following ALND.

Quantifying radiation in the axillary bed at the site of lymphedema surgical prevention.

PURPOSE: Immediate lymphatic reconstruction (ILR) is a procedure known to reduce the risk of lymphedema in patients undergoing axillary lymph node dissection (ALND). However, patients who receive adjuvant radiotherapy are at increased risk of lymphedema. The aim of this study was to quantify the extent of radiation at the site of surgical prevention. METHODS: We recently began deploying clips at the site of ILR to identify the site during radiation planning. A retrospective review was performed to identify breast cancer patients who underwent ILR with clip deployment and adjuvant radiation therapy from October 2020 to April 2022. Patients were excluded if they had not completed radiotherapy. The exposure and dose of radiation received by the site was determined and recorded. RESULTS: In a cohort of 11 patients, the site fell within the radiation field in 7 patients (64%) and received a median dose of 4280 cGy. Among these 7 patients, 3 had sites located within tissue considered at risk of oncologic recurrence and the remaining 4 sites received radiation from a tangential field treating the breast or chest wall. The median dose to the ILR site for the 4 patients whose sites were outside the radiation fields was 233 cGy. CONCLUSION: Our findings suggest that even when the site of surgical prevention was not within the targeted radiation field during treatment planning, it remains susceptible to radiation. Strategies for limiting radiation at this site are needed.

A Prospective Study of Radiation Therapy After Immediate Lymphatic Reconstruction: Analysis of the Dosimetric Implications.

PURPOSE: Axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) are the primary causes of breast cancer-related lymphedema (BCRL). Immediate lymphatic reconstruction (ILR) is a novel surgical procedure that reduces the incidence of BCRL after ALND. The ILR anastomosis is placed in a location thought to be outside the standard radiation therapy fields to prevent radiation-induced fibrosis of the reconstructed vessels; however, there is excess risk of BCRL from RNI even after ILR. The purpose of this study was to understand the radiation dose distribution in relation to the ILR anastomosis. METHODS AND MATERIALS: This prospective study included 13 patients treated with ALND/ILR from October 2020 to June 2022. A twirl clip deployed during surgery was used to identify the ILR anastomosis site during radiation treatment planning. All cases were planned using a 3D-conformal technique with opposed tangents and an obliqued supraclavicular (SCV) field. RESULTS: RNI deliberately targeted axillary Levels 1 to 3 and the SCV nodal region in 4 patients and was limited to Level 3 and SCV nodes in 9 patients. The ILR clip was located in Level 1 in 12 patients and Level 2 in 1 patient. In patients with radiation directed at only Level 3 and SCV, the ILR clip was still within the radiation field in 5 of these patients and received a median dose of 3939 cGy (range, 2025-4961 cGy). The median dose to the ILR clip was 3939 cGy (range, 139-4961 cGy) for the entire cohort. The median dose was 4275 cGy (range, 2025-4961 cGy) when the ILR clip was within any radiation field and 233 cGy (range, 139-280 cGy) when the clip was outside all fields. CONCLUSION: The ILR anastomosis was often directly irradiated with 3D-conformal techniques and received substantial radiation dose, even when the site was not deliberately targeted. Long-term analysis will help determine whether minimizing radiation dose to the anastomosis will decrease BCRL rates.

Acupuncture Treatment for Breast Cancer-Related Lymphedema: A Randomized Pilot Study.

Background: Methods of conservative management for breast cancer-related lymphedema (BCRL) are burdensome in terms of time, cost, and convenience. In addition, many patients are not candidates for surgical treatment. Preliminary results have demonstrated possible beneficial effects of acupuncture for patients with BCRL. In this small pilot study, we examined the safety and feasibility of an acupuncture randomized control trial (RCT) in this patient cohort, utilizing a battery of standardized clinical and patient-centered outcome measures. Methods and Results: Patients with BCRL were randomized 2:1 to the acupuncture (n = 10) or the control (n = 4) group. Patients received acupuncture to the unaffected extremity biweekly for 6 weeks. Feasibility was defined as enrollment ≥80%, completion of ≥9 of 12 acupuncture sessions per person, and ≥75% completion of three of three measurement visits. To inform a future adequately powered RCT, we describe within-group changes in patient-centered outcomes, including circumferential measurements, bioimpedance spectroscopy, perometry, cytokine levels, and patient quality of life. Adverse events were systematically tracked. Fourteen patients completed the study. Of those who received acupuncture (n = 10), 8 completed all 12 acupuncture sessions, and 2 patients completed 11 sessions. Ninety-three percent of all participants completed all three measurement visits. There was no consistent improvement in arm volumes. Inflammatory marker levels had inconclusive fluctuations among both groups. All patients receiving acupuncture demonstrated an improvement in their functional quality-of-life score. No severe adverse events occurred. Conclusions: A randomized controlled study of acupuncture for BCRL is feasible. The acupuncture intervention is acceptable in this population, without safety concerns in a small sample and warrants further investigation.

Tracking Symptoms of Patients With Lymphedema Before and After Power-Assisted Liposuction Surgery.

PURPOSE: Lymphedema negatively impacts patients from a psychosocial standpoint and consequently affects patient's quality of life. Debulking procedures using power-assisted liposuction (PAL) are currently deemed an effective treatment for fat-dominant lymphedema and improves anthropometric measurements as well as quality of life. However, there have been no studies specifically evaluating changes in symptoms related to lymphedema after PAL. An understanding of how symptoms change after this procedure would be valuable for preoperative counseling and to guide patient expectations. METHODS: A cross-sectional study was performed in patients with extremity lymphedema who underwent PAL from January 2018 to December 2020 at a tertiary care facility. A retrospective chart review and follow-up phone survey were conducted to compare signs and symptoms related to lymphedema before and after PAL. RESULTS: Forty-five patients were included in this study. Of these, 27 patients (60%) underwent upper extremity PAL and 18 patients (40%) underwent lower extremity PAL. The mean follow-up time was 15.5±7.9 months. After PAL, patients with upper extremity lymphedema reported having resolved heaviness (44%), as well as improved achiness (79%) and swelling (78%). In patients with lower extremity lymphedema, they reported having improved all signs and symptoms, particularly swelling (78%), tightness (72%), and achiness (71%). CONCLUSIONS: In patients with fat-dominant lymphedema, PAL positively impacts patient-reported outcomes in a sustained fashion over time. Continuous surveillance of postoperative studies is required to elucidate factors independently associated with the outcomes found in our study. Moreover, further studies using a mixed method approach will help us better understand patient's expectations to achieve informed decision and adequate treatment goals.

A 4-Year Institutional Experience of Immediate Lymphatic Reconstruction.

BACKGROUND: Up to one in three patients may go on to develop breast cancer-related lymphedema (BCRL) after treatment. Immediate lymphatic reconstruction (ILR) has been shown in early studies to reduce the risk of BCRL, but long-term outcomes are limited because of its recent introduction and institutions' differing eligibility requirements. This study evaluated the incidence of BCRL in a cohort that underwent ILR over the long term. METHODS: A retrospective review of all patients referred for ILR at the authors' institution from September of 2016 through September of 2020 was performed. Patients with preoperative measurements, a minimum of 6 months of follow-up data, and at least one completed lymphovenous bypass were identified. Medical records were reviewed for demographics, cancer treatment data, intraoperative management, and lymphedema incidence. RESULTS: A total of 186 patients with unilateral node-positive breast cancer underwent axillary nodal surgery and an attempt at ILR over the study period. Ninety patients underwent successful ILR and met all eligibility criteria, with a mean patient age of 54 ± 12.1 years and median body mass index of 26.6 kg/m 2 [interquartile range (IQR), 24.0 to 30.7 kg/m 2 ]. The median number of lymph nodes removed was 14 (IQR, eight to 19). Median follow-up was 17 months (range, 6 to 49 months). Eighty-seven percent of patients underwent adjuvant radiotherapy, and among them, 97% received regional lymph node irradiation. The overall rate of lymphedema was 9% at the end of the study period. CONCLUSIONS: With the use of strict follow-up guidelines over the long term, the authors' findings support that ILR at the time of axillary lymph node dissection is an effective procedure that reduces the risk of BCRL in a high-risk patient population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Variable Anatomy of the Lateral Upper Arm Lymphatic Channel: An Anatomical Risk Factor for Breast Cancer-Related Lymphedema.

BACKGROUND: The lateral upper arm channel is an accessory lymphatic pathway that drains the upper extremity by means of the deltopectoral groove and supraclavicular nodes, thereby bypassing the axilla. Its variable connectivity to the forearm has not been studied in vivo. METHODS: Indocyanine green (ICG) lymphography was performed preoperatively to map the superficial and functional arm lymphatics in breast cancer patients without clinical or objective evidence of lymphedema. A retrospective review was performed to extract demographic, ICG imaging, and surgical data. RESULTS: Sixty patients underwent ICG lymphography before axillary lymph node dissection between June of 2019 and October of 2020. In 59%, the lateral upper arm lymphatic channel was contiguous with the forearm (long bundle). In 38%, the lateral upper arm lymphatic channel was present but not contiguous with the forearm (short bundle). In 3%, the lateral upper arm pathway was entirely absent. Seven patients developed at least one sign of lymphedema during postoperative surveillance, of which 71% demonstrated the short bundle variant. CONCLUSION: Although the lateral upper arm pathway is most often present, its connections to the forearm are frequently absent (short bundle), which, in this pilot report, appears to represent a potential risk factor for the development of lymphedema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.

Creating a Policy for Coverage of Lymphatic Surgery: Addressing a Critical Unmet Need.

SUMMARY: This article describes the key stakeholders and process involved in developing an insurance policy in the United States to establish medical necessity criteria for lymphatic surgery procedures. Lymphedema is a chronic health issue that impacts over 1.2 million patients and is associated with lifelong health, economic, and psychosocial costs. Patients affected have been described as "medical nomads," as they often interface with multiple providers before receiving an accurate diagnosis and treatment. This underscores the lack of attention and understanding about this disease across all sectors of the medical system. Unlike nations including Sweden and the United Kingdom, which provide insurance coverage for treatment, the United States has lagged behind. As a country, we have neglected to fully recognize the consequences of inadequate treatment of lymphedema, including chronic morbidities such as loss of mobility, psychosocial sequelae, recurrent infections, and even death. Recently, the authors' lymphatic center had the unique opportunity to help develop a policy that merged their clinical experience, recently established lymphatic care center of excellence criteria, and third-party payer policy expertise. This experience spanned 1 year from June of 2018 to June of 2019. The authors identify how key partnerships helped fill evidentiary gaps that ultimately resulted in policy change.

Mapping the lymphatic system across body scales and expertise domains: A report from the 2021 National Heart, Lung, and Blood Institute workshop at the Boston Lymphatic Symposium.

Enhancing our understanding of lymphatic anatomy from the microscopic to the anatomical scale is essential to discern how the structure and function of the lymphatic system interacts with different tissues and organs within the body and contributes to health and disease. The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Recent advances in mapping components of the lymphatic system using state of the art single cell technologies, the identification of novel biomarkers, new clinical imaging efforts, and computational tools which attempt to identify connections between these diverse technologies hold the potential to catalyze new strategies to address lymphatic diseases such as lymphedema and lipedema. This manuscript summarizes current knowledge of the lymphatic system and identifies prevailing challenges and opportunities to advance the field of lymphatic research as discussed by the experts in the workshop.