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.
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.
Despite significant strides in lymphatic system imaging, the timely diagnosis of lymphatic disorders remains elusive. One main cause for this is the absence of standardized, quantitative methods for real-time analysis of lymphatic contractility. Here, we address this unmet need by combining near-infrared lymphangiography imaging with an innovative analytical workflow. We combined data acquisition, signal processing, and statistical analysis to integrate traditional peak and-valley with advanced wavelet time-frequency analyses. Decision theory was used to evaluate the primary drivers of attributable variance in lymphangiography measurements to generate a strategy for optimizing the number of repeat measurements needed per subject to increase measurement reliability. This approach not only offers detailed insights into lymphatic pumping behaviors across species, sex and age, but also significantly boosts the reliability of these measurements by incorporating multiple regions of interest and evaluating the lymphatic system under various gravitational loads. By addressing the critical need for improved imaging and quantification methods, our study offers a new standard approach for the imaging and analysis of lymphatic function that can improve our understanding, diagnosis, and treatment of lymphatic diseases. The results highlight the importance of comprehensive data acquisition strategies to fully capture the dynamic behavior of the lymphatic system.
Immediate lymphatic reconstruction (ILR) is recognized as a surgical approach used to reduce the risk of developing secondary lymphedema, and evidence demonstrating the efficacy of ILR is favorable. Our Lymphatic Center has become a centralized location offering ILR for the risk-reduction in breast cancer-related lymphedema (BCRL) in New England. Over the course of our experience, we made several modifications and adapted our approach to enhance the operative success of this procedure. These include advancements in our use of indocyanine green (ICG) imaging to identify baseline lymphatic anatomical variation, utilization of fluorescein isothiocyanate for lymphatic vessel visualization, application of the lymphosome concept to guide arm injection sites, verification of anastomotic patency (using ICG), localization of reconstruction to guide radiation therapy, incorporation of intraoperative tools to facilitate better anatomic visualization of the axilla, and addition of a lower extremity vein graft to mitigate venous-related complications. Collecting information from each surgery in a standardized manner, including intraoperative lymphatic channel measurements, and deploying clips for possible future radiation exposure, enables future studies on ILR patient outcomes. In this contribution, we aimed to share our institutional modifications with the surgical community to facilitate further adoption, conversation, and advancement of ILR for the risk-reduction in BCRL.
BACKGROUND: Medical students who attend institutions without plastic surgery residency programs are at a disadvantage in the plastic surgery match. We developed an educational program for medical students without home programs called Explore Plastic Surgery to provide an overview of the steps toward a career in plastic surgery. The purpose of this study was to assess the impact, utility, and success of the novel program.
METHODS: Pre- and postevent surveys were distributed to participants. Survey data were analyzed including participant demographics, perceptions of barriers unique to those without home programs, and the overall event utility.
RESULTS: Two hundred seventeen students registered for the program. Ninety-five participants completed the pre-event survey (44%), and of those, 57 participants completed the post-event survey (60%). There was an increase in understanding of the steps toward a career in plastic surgery ( P < 0.001), confidence in overcoming barriers ( P = 0.005), and level of comfort in reaching out to faculty for opportunities ( P = 0.01). There was a decrease in the perceived negative impact that attending medical schools without a home program will have on their abilities to pursue careers in plastic surgery ( P = 0.006).
CONCLUSIONS: After the event, participants demonstrated an increase in their confidence in overcoming barriers and a decrease in their perceptions that attending an institution without a home program would negatively impact their ability to pursue plastic surgery. Initiatives focused on early exposure and recruitment of medical students may be important to promote accessibility and diversity within plastic surgery.
OBJECTIVE: To assess changes in noncontrast magnetic resonance imaging (MRI)-based biomarkers after upper extremity lymphedema surgery.
METHODS: We retrospectively identified secondary upper extremity lymphedema patients who underwent vascularized lymph node transplant (VLNT), debulking lipectomy, or VLNT with a prior debulking (performed separately). All patients with both preoperative and postoperative MRIs were compared. An MRI-based edema scoring system was used: 0 (no edema), 1 (<50% fluid from myofascial to dermis), and 2 (≥50% fluid from myofascial to dermis). Edema scores and subcutaneous thickness (ST) were obtained along four quadrants across the upper and lower third of the arm and forearm each-for a total of 16 anatomical locations-and compared before and after surgery. Net changes in edema scores and ST were then correlated with Lymphoedema Quality-of-Life Questionnaire scores, L-Dex (bioimpedance), and limb volume difference by perometry.
RESULTS: Patients who underwent lymphatic surgeries between January 2017 and December 2022 and successfully completed preoperative and postoperative MRI were included, resulting in a total of 33 unilateral secondary upper extremity lymphedema patients m(mean age, 63 ± 14 years; 32 female). The median postoperative follow-up times were 12.5 months (range, 6-19 months) for VLNT, 13.5 months (range, 12-40 months) for debulking, and 12.0 months (range, 12-24 months) for patients who underwent VLNT after debulking surgery. There was a decrease in mean ST in 15 of 16 anatomical segments of the upper extremity after debulking (P < .001), and the edema score increased in 7 of 16 segments (P ≤ .001-.020). Edema stage did not change in patients who underwent VLNT only or VLNT after debulking. ST decreased only along the radial forearm in patients who underwent VLNT after debulking despite an improvement in the Lymphoedema Quality-of-Life Questionnaire score in the former group. There was correlation between a decrease in ST with a decrease in volume within the debulking group (r = 0.79; P < .001). A decrease in ST also correlated with improved lymphedema quality of life questionnaires in the debulking group (r = 0.49; P = .04).
CONCLUSIONS: A decrease in ST was demonstrated in most anatomical segments after liposuction debulking, whereas edema stage was increased. Fewer changes were seen with VLNT, possibly a reflection of more gradual changes within this short follow-up period, with the radial forearm potentially revealing the earliest response.
BACKGROUND: Variations of hand and forearm lymphatic drainage to upper-arm lymphatic pathways may impact the route of melanoma metastasis. This study compared rates of lymphatic drainage to epitrochlear nodes between anatomic divisions of the hand and forearm to determine whether the anatomic distribution of hand and forearm melanomas affects the likelihood of drainage to epitrochlear lymph nodes.
METHODS: Using a single-institution lymphoscintigraphy database, we identified all patients with cutaneous melanoma on the hand and forearm. A body-map two-dimensional coordinate system was used to classify cutaneous melanoma sites between radial-ulnar and dorsal-volar divisions. Sentinel lymph nodes (SLNs) visualized on lymphoscintigraphy were recorded. Proportions of patients with epitrochlear SLNs were compared between anatomic divisions using χ2 analysis.
RESULTS: Of 3628 upper extremity cutaneous melanoma patients who underwent lymphatic mapping with lymphoscintigraphy, 1400 met inclusion criteria. Twenty-one percent of patients demonstrated epitrochlear SLNs. Epitrochlear SLNs were observed in 27% of dorsal forearm melanomas and 15% of volar forearm melanomas (p < 0.001). Epitrochlear SLNs were observed in 31% of ulnar forearm melanomas and 17% of radial forearm melanomas (p < 0.001).
CONCLUSIONS: Higher proportions of dorsal and ulnar forearm melanomas have epitrochlear SLNs. Metastasis to epitrochlear SLNs may be more likely from melanomas in these respective forearm regions.
BACKGROUND: Lymphatic drainage from the arm may be altered after axillary lymph node dissection (ALND). Understanding these alterations is important as they may change standard surgical and radiation treatment in recurrent breast cancer or upper extremity skin cancers, including melanoma.
METHODS: Utilizing a single-institution planar and single photon emission computed tomography/computed tomography lymphoscintigraphy database, we identified patients with a diagnosis of upper extremity cutaneous melanoma from 2008 to 2023 who previously underwent ALND for cancer treatment and did not develop upper extremity cancer-related lymphedema. ALND patients were matched to control patients presenting with cutaneous melanomas at the same anatomic sites. Sentinel lymph nodes (SLNs) were compared between both groups.
RESULTS: Of 3628 upper extremity melanoma cutaneous patients, 934 met inclusion criteria, including 22 ALND and 912 control patients. Level I axillary SLN drainage was observed in 98% of controls and 27% of ALND patients (p < 0.001). Level II axillary SLN drainage was observed in 3% of controls and 27% of ALND patients (p < 0.001). Level III axillary SLN drainage was observed in 1% of controls and 32% of ALND patients (p < 0.001). Epitrochlear SLN drainage was observed in 9% of controls and 32% of ALND patients, respectively (p < 0.046). Brachial SLN drainage was observed in 4% of controls and 23% of ALND patients (p < 0.001).
CONCLUSIONS: Distinct changes in functional lymphatic drainage were seen between the arms of patients who previously underwent ALND versus control patients. Levels II and III axillary, epitrochlear, and brachial nodes are possible sites of metastatic disease that should be considered in patients with a prior ALND.
OBJECTIVE: We evaluated whether superficial lymphatic anatomy and functional lymph node drainage are symmetric between the right and left upper extremities of healthy female volunteers, and if handedness is associated with symmetry of superficial lymphatic anatomy.
BACKGROUND: Symmetry of lymphatic anatomy has been assumed historically. This assumption of individual anatomic symmetry is being utilized clinically and in research without validation.
METHODS: 36 normal female volunteers underwent bilateral indocyanine green (ICG) lymphography and lymphoscintigraphy of the upper extremities. Eight collecting vessel pathways of each upper extremity were mapped on ICG lymphography. 13 lymph node groups were visualized on lymphoscintigraphy. Symmetry of lymphatic anatomy and functional drainage were established by comparing the right and left extremities of each participant. Hand dominance was assessed by hand grip strength on a hand dynamometer.
RESULTS: Among the 36 participants, 10 (28%) showed symmetry of all eight upper extremity lymphatic pathways with ICG. However, only 1 (3%) participant demonstrated complete symmetry amongst the 13 lymph node groups. Total symmetry of lymphatic channels was observed on ICG in seven (39%) participants with hand dominance and three (17%) participants without hand dominance (X2 = 2.215, P = 0.137).
CONCLUSION: Lymphatic anatomy and functional drainage of the upper extremities are not consistently symmetric. Functional nodal drainage as demonstrated by lymphoscintigraphy shows less symmetry than anatomic studies of lymphatic channels using ICG. Symmetric lymphatic anatomy does not appear to correlate with hand dominance. These findings challenge the prevailing assumption of left-right lymphatic symmetry.
