Lymphatic System Research Articles

Synergistic effects of mTOR inhibitors with VEGFR3 inhibitors on the interaction between TSC2-mutated cells and lymphatic endothelial cells.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting the lung, kidney, and lymphatic system with a molecular mechanism of tuberous sclerosis complex 2 (TSC2) mutations. Vascular endothelial growth factor D (VEGF-D), a ligand for vascular endothelial growth factor receptor 3 (VEGFR3), is a diagnostic biomarker of LAM and is associated with lymphatic circulation abnormalities. This study explored the interaction between LAM cells and lymphatic endothelial cells (LECs) and the effects of rapamycin on this interaction, which may help to identify new targets for LAM treatment. This study used direct and indirect cocultures of TSC2-null cells and LECs. The xenograft model was applied to explore the therapeutic feasibility. Single-cell sequencing revealed increased LECs in the lungs of LAM patients through activation of pathways involved in lymphangiogenesis. TSC2-null cells attracted LECs and promoted tube formation. VEGF-D/VEGFR3 was a key mediator of the above interaction. Rapamycin can directly inhibit recruitment but not the tube formation of LECs in vitro. The combination of rapamycin with VEGFR3 inhibitors not only enhanced the effect of rapamycin but also inhibited lymphatic related manifestations including the tube formation and the lymphatic metastasis. Our findings demonstrated that LAM cells recruit LECs and promote tube formation via VEGF-D/VEGFR3. Rapamycin only partially blocked this interaction. The synergistic effects of rapamycin and VEGFR3 inhibitors suggest a novel strategy for the treatment of LAM and other TSC2-mutated diseases.

Understanding the Lymphatic System: Tissue-on-Chip Modeling.

The lymphatic vasculature plays critical roles in maintaining fluid homeostasis, transporting lipid, and facilitating immune surveillance. A growing body of work has identified lymphatic dysfunction as contributing to the severity of myriad diseases and to systemic inflammation, as well as modulating drug responses. Here, we review efforts to reconstruct lymphatic vessels in vitro toward establishing humanized, functional models to advance understanding of lymphatic biology and pathophysiology. We first review lymphatic endothelial cell biology and the biophysical lymphatic microenvironment, with a focus on features that are unique to the lymphatics and that have been used as design parameters for lymphatic-on-chip devices. We then discuss the state of the art for recapitulating lymphatic function in vitro, and we acknowledge limitations and challenges to current approaches. Finally, we discuss opportunities and the need for further development of microphysiological lymphatic systems to bridge the gap in model systems between lymphatic cell culture and animal physiology.

Evaluation of the safety profile of amivantamab based on real-world evidence: a call to vigilance

ABSTRACT Background Amivantamab has been approved for EGFR exon 20 insertion-mutated non-small-cell lung cancer. The aim of this study was to perform an in-depth analysis of its safety profile. Research design and methods Safety reports were collected from the database of the Food and Drug Administration Adverse Event Reporting System from April 2021 to September 2023, and the reporting odds ratio (ROR) method was used to detect potential safety signals. Mobocertinib, an agent with similar properties to amivantamab, served as a control for comparison. Results A total of 88 safety signals were detected, most of which were novel. In comparison with mobocertinib, amivantamab appeared to cause more injury, poisoning, and procedural complications (ROR = 15.54, 95% CI 10.25–23.58); respiratory, thoracic, and mediastinal disorders (ROR = 1.92, 95% CI 1.57–2.34); infections and infestations (ROR = 1.39, 95% CI 1.09–1.76); blood and lymphatic system disorders (ROR = 9.57, 95% CI 6.17–14.84); and immune system disorders (ROR = 6.41, 95% CI 3.14–13.12). Moreover, amivantamab was associated with higher risks of thrombosis events, bone marrow suppression, skin and soft tissue infection, deterioration of respiratory symptoms, and noninfectious pneumonitis. Conclusion The safety profile of amivantamab requires attention; particularly, monitoring of the adverse drug events described above is necessary during its administration.

Abdominal lymphatic malformations in children: case series.

Lymphatic Malformations (LMs) are benign congenital malformations of the lymphatic system that commonly involve the abdomen in children (mesentery of the small intestine and omentum). The management of these malformations is not unique. 7 children with different ages (range: newborn to 14 years), diagnosis was incidental in some cases, while in others for abdominal pain. All patients underwent abdominal ultrasound and Magnetic Resonance Imaging (MRI). Laparoscopy for diagnosis was useful in 4 cases. Treatment was: conservative in 1 child, laparoscopic excision in 3 patients, laparotomic excision in 3 cases. At follow up we observed recurrence in a case that required integrated treatment and bowel occlusion after excision in 1 case. This benign malformations may not cause any symptoms to patient. The goal of treatment is to maintain organ function, preserve aesthetic integrity and complications control. Management of these patients could be varied: the best approach should be evaluated on the basis of the patient.

P0088 3D tissue-level analysis of intestinal T cell dynamics reveals dual effects of etrasimod on recruitment and tissue exit in experimental colitis

Abstract Background Sphingosin-1-phosphate (S1P) receptor (S1PR) agonists are a novel class of anti-trafficking agents approved for the treatment of ulcerative colitis. These compounds induce T lymphocyte sequestration in secondary lymphoid organs, reducing their availability in peripheral blood and presumably in inflamed intestinal tissue. However, direct evidence for their effects on T cell dynamics within intestinal tissue is lacking. Moreover, while S1PR-dependent mechanisms regulate T cell egress from the gut, it remains unclear whether S1PR agonists modulate this process. This limited understanding of tissue-specific effects presents a crucial barrier to comprehending their full therapeutic mechanism. Methods We developed a comprehensive volumetric imaging platform to investigate tissue-level mechanisms of colitis within the complex three-dimensional architecture of the intestine. Using the T cell transfer colitis model, mice were treated with etrasimod or vehicle control. Full-thickness colon samples underwent tissue clearing and whole-mount immunofluorescence for T cell markers. Advanced light-sheet and volumetric confocal microscopy, combined with machine learning-based image analysis, enabled three-dimensional reconstruction of T cell distributions and lymphatic networks, allowing for quantitative histocytometry and spatial mapping of immune cell dynamics. Results T cell transfer colitis induced substantial lymphocyte infiltration in the colon, with T cells forming both distinct clusters and diffuse distributions throughout the tissue. The presence of numerous T cells within lymphatic vessels indicated active tissue egress, suggesting that T cell accumulation reflects a dynamic balance between recruitment and exit (Figure 1). Etrasimod treatment not only reduced overall T cell infiltration but also markedly altered their spatial distribution pattern. Notably, we observed a decreased proportion of T cells within lymphatic vessels, coupled with increased accumulation of T cells in proximity to lymphatic structures, indicating a previously unrecognized effect on tissue exit dynamics. Conclusion Our advanced volumetric imaging approach revealed novel insights into a potential dual mechanism of etrasimod in inflammatory bowel disease. Beyond reducing lymphocyte recruitment, etrasimod appears to create a tissue exit block, effectively trapping T cells within the intestinal compartment. These findings raise important questions about how enforced tissue residency influences local inflammatory circuits and may guide optimization of therapeutic strategies.

Less Is More: Donor Engineering of a Stable Molecular Dye for Bioimaging in the NIR-IIb Window.

Fluorescence molecular imaging aims to enhance clarity in the region of interest, particularly in the near-infrared IIb window (NIR-IIb, 1500-1700 nm). To achieve this, we developed a novel small-molecule dye, named DA-5, based on classic cyanine dyes (heptamethine or pentamethine is essential for wavelengths beyond 1000 nm). By reducing excessive polymethine to a single methine and disrupting symmetry to form an asymmetric donor-π-acceptor (D-π-A) architecture, we enhanced the donor's electron-donating capability, yielding emission at 1088 nm. DA-5 exhibits superior properties, including excellent chemo- and photostability, resistance against solvatochromism-caused quenching, and antiaggregation in aqueous solution. With a large Stokes shift (241 nm) and high brightness (321 M-1 cm-1), DA-5 enables high-performance imaging of the lymphatic system, intestinal vessels, whole-body angiography, and cerebral and hindlimb microvasculature in NIR-IIb. This molecular design strategy offers a promising platform for advancing in vivo biophotonics.

TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity

In situ vaccination (ISV) triggers antitumor immune responses using the patient’s own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which CR108 boosts and sustains the antitumor responses induced by the cisplatin-released neoantigens. In mouse models, the cisplatin+CR108 combination significantly outperformed cisplatin or CR108 alone in abrogating established 4T1 and B16 tumors. The synergistic antitumor effects of cisplatin and CR108 were accompanied by markedly increased tumor tertiary lymphatic structures (TLS) formation, higher levels of type I and III interferons and TNF-α in serum, augmented T and B lymphocyte infiltration, antigen-presenting cell activation, as well as reduced functionally of exhausted T cells. Single-cell sequencing analysis uncovered a potential pathway for TLS to serve as a reservoir for functional antitumor effector T cells. Furthermore, cisplatin+CR108 combo therapy, but neither cisplatin nor CR108 alone, effectively inhibited the growth of treated 4T-1 tumor in an effector T cell-dependent manner. Notably, the combo therapy also suppressed the growth of distant untreated 4T-1 tumors, demonstrating systemic antitumor effects. Moreover, combo-therapy led to full regression of 4T-1 tumors in a large percentage of mice, who became strongly resistant to secondary tumor challenge, a clear indication of antitumor immunological memory. The cisplatin+CR108 combo therapy holds promise in converting “cold” tumors into “hot” ones and eliciting robust antitumor immune responses in vivo.

A multiresolution approach with method-informed statistical analysis for quantifying lymphatic pumping dynamics

Despite significant strides in lymphatic system imaging, the timely diagnosis of lymphatic disorders remains elusive. This is driven by the absence of standardized, non-invasive, reliable, quantitative methods for real-time functional analysis of lymphatic contractility with adequate spatial and temporal resolution. Here, we address this unmet need by integrating near-infrared fluorescence lymphangiography imaging with an innovative analytical workflow that combines data acquisition, signal processing, and statistical analysis to integrate traditional peak-and-valley analysis with advanced wavelet time-frequency analyses. Variance component analysis was used to evaluate the drivers of variance attributable to each experimental variable for each lymphangiography measurement type. Generalizability studies were used to assess the reliability of measured parameters and how reliability improves as the number of repeat measurements per subject increases. This allowed us to determine the minimum number of repeat measurements needed per subject for acceptable 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. For example, the reliability of the peak-and-valley analysis of human lymphatic vessels was increased 3-fold using the described approach. 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.

The Impact of Relaxation Massage Prior to Bedtime on Sleep Quality and Quantity in People with Symptoms of Chronic Insomnia: A Home-Based Sleep Study.

Background/Objectives: Manual massage is an effective treatment approach for reducing general stress and promoting an overall sense of well-being. Relaxation massage aims to alleviate psychophysiological tension, enhance both blood and lymphatic circulation, and promote mental and physical relaxation. It is particularly beneficial for those with anxiety-related symptoms (such as generalized anxiety disorder and social anxiety) and sleep disorders, aiming to improve calmness and promote sleepiness. Aims: The purpose of the present study was to assess the effectiveness of a single session of relaxation massage prior to bedtime on sleep quality and quantity indices in individuals with symptoms of chronic insomnia. Methods: In total, 20 (N = 20) healthy individuals (aged 25.5 ± 12.0 years; 6F/14M) with a score on the Athens Insomnia Scale of ≥16 participated under three different conditions over one week apart: (1) a 45 min relaxation massage condition (REL), (2) a 45 min sham massage condition (PLA), and (3) a control condition with no massage. Sleep activity was monitored using a portable polysomnographic system. Results: A statistically significant effect was observed between sleep efficiency across the three sessions (p = 0.034), with a notable effect in the relaxation massage (REL) session (p = 0.045). Additionally, sustained sleep efficiency showed a statistically significant difference among the sessions (p = 0.005). Conclusions: Relaxation massage prior to bedtime could be used as an effective and safe non-pharmacological approach for improving sleep efficiency and potentially restoring the fragmented sleep of individuals with symptoms of insomnia. Trial registration number: The trial was registered at clinicaltrials.gov as NCT06781866.

Targeted Modulation of the Meningeal Lymphatic Reverse Pathway for Immunotherapy of Breast Cancer Brain Metastases.

Treatment of tumor brain metastases remains challenging due to the ineffectiveness of drugs in crossing the blood-brain barrier (BBB). Here, we proposed a potential strategy to target and modulate the meningeal lymphatic system for immunotherapy of breast cancer brain metastases (BCBM) through peripheral administration. CT/fluorescence dual-modality imaging demonstrated that the phospholipid nanoprobe (α-PLNPs) through intracisternal magna injection effectively labeled and long-range tracked the meningeal lymphatic pathway from meningeal lymphatic vessels (MLVs) to periphery drainage cervical lymph nodes (CLNs). Interestingly, the reverse pathway from CLNs to MLVs was also successfully labeled with α-PLNPs through cervical subcutaneous injection, facilitating the noninvasive delivery of immunomodulators to the meningeal lymphatics. Given this, we used melittin-carrying α-M-PLNPs to trigger the modulation of the meningeal lymphatic reverse pathway, which effectively prevents BCBM and prolongs the survival of mice through activating the antigen-presenting cells in the CLNs and promoting the migration of CD8+ T cells into the metastatic brain tumors. This study highlights the potential of the meningeal lymphatic reverse pathway for the immunotherapy of BCBM, which holds great promise for central nervous system disease therapy without the need for drug delivery via BBB.

The role of the lymphatic system in brain clearance mechanisms implications for neurodegenerative disorders

The lymphatic system, traditionally associated with immune surveillance and fluid homeostasis, has emerged as a pivotal player in maintaining brain health. Recent discoveries highlight the brain’s unique clearance mechanisms, particularly the glymphatic system and meningeal lymphatic vessels, in removing metabolic waste and facilitating neuroimmune communication. Dysfunction in these pathways has been implicated in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). This review explores the anatomy and physiology of the lymphatic system in the brain, its role in waste clearance, and its implications for neurodegenerative disorders, drawing on recent advances in imaging and molecular research.

Tissue-Engineered Therapeutics for Lymphatic Regeneration: Solutions for Myocardial Infarction and Secondary Lymphedema.

The lymphatic system, which regulates inflammation and fluid homeostasis, is damaged in various diseases including myocardial infarction (MI) and breast-cancer-related lymphedema (BCRL). Mounting evidence suggests that restoring tissue fluid drainage and clearing excess immune cells by regenerating damaged lymphatic vessels can aid in cardiac repair and lymphedema amelioration. Current treatments primarily address symptoms rather than underlying causes due to a lack of regenerative therapies, highlighting the importance of the lymphatic system as a promising novel therapeutic target. Here cutting-edge research on engineered lymphatic tissues, growth factor therapies, and cell-based approaches designed to enhance lymphangiogenesis and restore lymphatic function is explored. Special focus is placed on how therapies with potential for immediate lymphatic reconstruction, originally designed for treating BCRL, can be applied to MI to augment cardiac repair and reduce heart failure risk. The integration of these novel treatments can significantly improve patient outcomes by promoting lymphatic repair, preventing pathological remodeling, and offering new avenues for managing lymphatic-associated diseases.

Anatomical Studies on the Morphology and Topography of Cavity Lymphnodes in Pigs

The lymphatic system, supported by the lymphatic vessels, is a vascular network in higher vertebrates, having essential roles, such as regulating tissue pressure, monitoring the immune system and absorbing fats from the diet. The lymphatic vessels constitute an unidirectional system that transports fluids and proteins, taking them from the interstitial space and returning them to the bloodstream. Objectives: The objectives pursued in this study are the following: to identify the topography of the main cavity lymph nodes and the morphological and topographic variants that may occur; to identify the main interspecific histological characteristics of vessels and lymph nodes in pigs. Materials and methods: The study was carried out on 20 animals weighing 25-30 kg, aged about 3.5 months, of both sexes. They came from private breeders. Ultrasonographic investigations were also performed on half of them. The macro- and microscopic anatomical studies as well as the ultrasonographic investigations were performed at the Faculty of Veterinary Medicine in Bucharest. For macroscopic and topographic analysis, lymph nodes in both the thoracic and abdominal cavities were examined "in situ". Results. Caudal mediastinal lymph nodes were always fewer in number (between one and three). They were associated with the esophagus, immediately behind the tracheobronchial and ventral lymph nodes of the aorta. The afferents originated from the pericardium, the caudal part of the mediastinum and the corresponding part of the esophagus. The efferents connected to the tracheobronchial lymph nodes or could also approach some thoraco-aortic lymph nodes. The lumbo-aortic lymph nodes were located on the lateral surfaces of the aorta, starting from the diaphragmatic orifice to the origin of the deep iliac circumflex artery. The iliac lymphocenters were represented by large lymph nodes that formed a bundle at the origin of the celiac artery. Colic lymph nodes were located along the path of the right colonic artery. Splenic lymph nodes were placed on the path of the homonymous vessels. Their topography was between the aorta and the hilum of the spleen. In this sector there could be 2-4 lymph nodes, but there were others (2-5) located along the upper quarter of the spleen. The jejunal lymph nodes formed a double chain in the middle of the jejuno-ileum meso, about 30 cm long. The caudal mesenteric lymph nodes were reduced, located dorsally by the descending colon on the path of the caudal mesenteric artery. Conclusions. In the case of mediastinal lymph nodes, the anterior ones are present, but their topography differs significantly from individual to individual. The most important groups of visceral lymph nodes are jejunal and colic. The most important parietal lymphocenter is the ileosacral one. In it, we were able to describe for the first time some individual variants, namely: lateral iliac lymph nodes dominant in volume compared to the medial ones, the absence in some cases (10%) of anorectal lymph nodes in some specimens, in which, however, a compensation was observed by the development of a chain of small units on the path of the median sacral artery.

Disorders of Lymphatic Architecture and Flow in Critical Illness.

To provide a narrative review of disordered lymphatic dynamics and its impact on critical care relevant condition management. Detailed search strategy using PubMed and Ovid Medline for English language articles (2013-2023) describing congenital or acquired lymphatic abnormalities including lymphatic duct absence, injury, leak, or obstruction and their associated clinical conditions that might be managed by a critical care medicine practitioner. Studies that specifically addressed abnormalities of lymphatic flow and their management were selected. The search strategy time frame was limited to the last 10 years to enhance relevance to current practice. Relevant descriptions or studies were reviewed, and abstracted data were parsed into structural or functional etiologies, congenital or acquired conditions, and their management within critical care spaces in an acute care facility. Abnormal lymph flow may be identified stemming from congenital lymphatic anomalies including lymphatic structure absence as well as acquired obstruction or increased flow from clinical entities or acute therapy. Macro- and microsurgical as well as interventional radiological techniques may address excess, inadequate, or obstructed lymph flow. Patients with deranged lymph flow often require critical care, and those who require critical care may concomitantly demonstrate deranged lymph flow that adversely impacts care. Critical care clinicians ideally demonstrate functional knowledge of conditions that are directly related to, or are accompanied by, deranged lymphatic dynamics to direct timely diagnostic and therapeutic interventions during a patient's ICU care episode.

A comprehensive review of computational diagnostic techniques for lymphedema.

Lymphedema is localized swelling due to lymphatic system dysfunction, often affecting arms and legs due to fluid accumulation. It occurs in 20% to 94% of patients within 2 to 5 years after breast cancer treatment, with around 20% of women developing breast cancer-related lymphedema (BCRL). This condition involves the accumulation of protein-rich fluid in interstitial spaces, leading to symptoms like swelling, pain, and reduced mobility that significantly impact quality of life. The early diagnosis of lymphedema helps mitigate the risk of deterioration and prevent its progression to more severe stages. Healthcare providers can reduce risks through exercise prescriptions and self-manual lymphatic drainage techniques. Lymphedema diagnosis currently relies on physical examinations and limb volume measurements, but challenges arise from a lack of standardized criteria and difficulties in detecting early stages. Recent advancements in computational imaging and decision support systems have improved diagnostic accuracy through enhanced image reconstruction and real-time data analysis. The aim of this comprehensive review is to provide an in-depth overview of the research landscape in computational diagnostic techniques for lymphedema. The computational techniques primarily include imaging-based, electrical, and machine learning approaches, which utilize advanced algorithms and data analysis. These modalities were compared based on various parameters to choose the most suitable techniques for their applications. Lymphedema detection faces challenges like subtle symptoms and inconsistent diagnostics. The research identifies Bioimpedance Spectroscopy (BIS), Kinect sensor and Machine Learning integration as the promising modalities for early lymphedema detection. BIS can effectively identify lymphedema as early as four months post-surgery with sensitivity of 44.1% and specificity of 95.4% in diagnosing lymphedema whereas in Machine learning, Artificial Neural Network (ANN) achieved an impressive average cross-validation accuracy of 93.75%, with sensitivity at 95.65% and specificity at 91.03%. Machine learning and imaging can be integrated into clinical practice to enhance diagnostic accuracy and accessibility.

Thermo-responsive Fluorescent Nanopolymer Delivery Platform for Treatment of Diffuse Large B-cell Lymphoma (DLBCL).

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive diffuse malignant proliferative disease of the lymphatic system. Patients usually present with progressive lymph node enlargement and/or extra-lymph node lesions and require early treatment upon diagnosis. Most of the patients are in stage III or IV at the time of diagnosis and about 40% of the patients are difficult to cure. In this study, we developed a novel drug delivery platform using poly(ε-caprolactone)-tetraphenylethylene (PCL-TPE). This fluorescent polymer, combined with a solid-state dye, exhibits temperature-dependent fluorescence. We loaded the synthesized ethyl 2-amino-4-(4-methylthiophen-2-yl)-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate (compound 1) onto PCL-TPE, creating PCL-TPE@1. By treating human lymphoma cells, we found that PCL-TPE@1 was able to effectively reduce the migratory ability of lymphoma cells by inhibiting the expression of PRMT6. This platform is easy to synthesize, offers thermo-responsive fluorescence, flexibility, and biocompatibility, making it suitable for biomedical drug delivery and smart devices.

Lymphatic collection and cell isolation from mouse models for multiomic profiling.

Premetastatic cancer cells often spread from the primary lesion through the lymphatic vasculature and, clinically, the presence or absence of lymph node metastases impacts treatment decisions. However, little is known about cancer progression via the lymphatic system or of the effect that the lymphatic environment has on cancer progression. This is due, in part, to the technical challenge of studying lymphatic vessels and collecting lymph fluid. Here we provide a step-by-step procedure to collect both lymph and tumor-draining lymph in mouse models of cancer metastasis. This protocol has been adapted from established methods of lymph collection and was developed specifically for the collection of lymph from tumors. The approach involves the use of mice bearing melanoma or breast cancer orthotopic tumors. After euthanasia, the cisterna chyli and the tumor are exposed and viewed using a stereo microscope. Then, a glass cannula connected to a 1 mL syringe is inserted directly into the cisterna chyli or the tumor-draining lymphatics for collection of pure lymph. These lymph samples can be used to analyze the lymph-derived cancer cells using highly sensitive multiomics approaches to investigate the impact of the lymph environment during cancer metastasis. The procedure requires 2 h per mouse to complete and is suitable for users with minimal expertise in small animal handling and use of microsurgical tools under a stereo microscope.

Modelling pacemaker oscillations in lymphatic muscle cells: lengthened action potentials by two distinct system effects.

Lymphatic system failures contribute to cardiovascular and various other diseases. A critical function of the lymphatic vascular system is the active pumping of fluid from the interstitium back into the blood circulation by periodic contractions of lymphatic muscle cells (LMCs) in the vessel walls. As in cardiac pacemaking, these periodic contractions can be interpreted as occurring due to linked pacemaker oscillations in the LMC membrane potential (M-clock) and calcium concentration (C-clock). We previously reported a minimal model of synchronized dual-clock-driven oscillations. While this qualitatively replicated the period of oscillations under different conditions, it did not replicate the action potential shape as it varied under those conditions, particularly as regards the extent or lack of a systolic plateau. Here, we modify the model to replicate the plateau behaviour. Using phase-plane analysis we show two qualitatively different dynamical mechanisms that could account for plateau formation, one largely M-clock-driven, the other largely C-clock-driven. The second case occurs with the introduction of a ryanodine receptor; in both cases, we find improved predictions for calcium levels. With enhanced fidelity to the experimental data, the improved model has the potential to help determine opportunities for pharmacological treatment of lymphatic system pumping defects.

Effective Management Strategies for Primary Lymphedema of the Lower Extremities: Integrating Conservative and Surgical Therapies in Early and Late Stages.

Lymphedema, a debilitating characterized by localized fluid retention and tissue swelling, results from abnormalities in the lymphatic system. In the case of primary lymphedema, this condition is attributed to malformations in lymphatic vessels or nodes, and it is marked by a relentless progression leading to irreversible tissue fibrosis after repetitive inflammation. Many questions regarding its treatment, such as the choice of the type of intervention and the timing, still remain unanswered. This study aims to present our comprehensive approach to treat this challenging condition. To elucidate our approach, we conducted a retrospective chart review of 42 patients treated for primary lymphedema at 3 hospitals between July 2010 and December 2022. The study included two patient groups, those with early-stage disease (20) and those in the advanced stages (22). We outline our algorithm, based on our clinical experience in Taiwan. Patients were followed for at least 12 months post-treatment, and assessments were made, including photographic evidence. A total of 42 patients participated in our study: 20 in the early stage and 22 in the late stage. Our approach yielded significant functional improvements and symptom regression in both groups. In the early-stage cohort, all 20 patients underwent VLNT procedures and SAL, with 15 (75%) undergoing unilateral procedures and 5 (25%) bilateral. Among the advanced-stage patients, 12 (54.5%) were treated with the modified Charles' procedure, and 10 (45.5%) with RRPP. The outcomes showed an average circumference reduction of 4.1 cm (2.9-5.3) after VLNT and liposuction. Reductions were noted at various levels: 5.7 cm (4.6-6.8) at mid-thigh, 4.3 cm (2.5-6.1) at mid-calf, 3.5 cm (2.7-4.3) at the ankle, and 1.4 cm (0.7-2.1) at mid-foot. Tonicity decreased by 5.9% (5.2-6.6), indicating significant tissue softening. Tissue removal averaged 3.7 kg (2.9-4.5) after the modified Charles' procedure and 2.6 kg (2.3-2.9) after RRPP. Patients experienced a mean of 3 (2-4) episodes of cellulitis per year, with no cellulitis in early-stage treated limbs during the follow-up period. Complications were minimal, including 4 partial skin graft losses that healed with conservative treatment and 3 postoperative infections after the modified Charles' procedure, treated successfully with antibiotics. No major complications were reported at the lymph node flap donor site. Primary lymphedema poses a considerable challenge, primarily due to its relentless progression if left untreated. The existing literature offers limited guidance on its management. Our algorithm, developed over years of experience, aims to fill this gap. By integrating surgical and conservative interventions, as well as individualized patient follow-up, we provide a comprehensive framework for managing both early and late- stage cases.

Unusual Benefit of Lumbar Sympathetic Block in Filarial Lymphedema

Lymphatic filariasis, commonly known as elephantiasis, is a neglected tropical disease which causes hidden damage to the lymphatic system resulting in disfigurement, suffering, and poor quality of life. Lumbar sympathetic block is routinely used by pain physicians for vascular insufficiency, sympathetically mediated pain, hyperhidrosis, and discogenic pain as usual indications. There is no report in literature of performing a sympathetic block for filarial lymphedema. The author would like to report this case of a patient of filarial lymphedema and pain who benefitted with a lumbar sympathetic block.