The lymphedema patient experience within the healthcare system: a cross-sectional epidemiologic assessment.

Lymphedema is a progressive lymphatic disease that potentiates physical and psychosocial distress. Despite its impact, patients reportedly encounter lymphatic ignorance throughout the healthcare system. This cross-sectional study aims to summarize clinical characteristics and interactions of lymphedema patients within the healthcare system. Two lymphedema patient cohorts were included: The Global Registry Analysis Cohort included lymphedema patients who contributed to an international digital lymphatic registry and the Interactions Cohort included patients who initiated a questionnaire about interactions with the medical system. The global registry was used to obtain demographic and clinical characteristics from affiliated lymphedema patients. A 23-item online questionnaire on healthcare experiences and satisfaction with lymphatic healthcare was then distributed to the Interactions Cohort. Complete responses were obtained from 2474 participants. Participants were a mean age of 57.5 ± 16.1 years and 51.4% had a cancer history. Participants reported substantial delays in diagnosis and treatment. Cancer-related and non-cancer-related lymphedema patients reported similar levels of perceived physician disinterest in their lymphedema; however, non-cancer-related lymphedema patients reported more care dissatisfaction. Ultimately, patients continue to face delays in lymphedema diagnosis and treatment. We developed an evidence-based model highlighting areas of reform needed to improve lymphatic education and healthcare.

Spike Reliability is Cell-Type Specific and Shapes Excitation and Inhibition in the Cortex.

Neurons encode information in the highly variable spiking activity of neuronal populations, so that different repetitions of the same stimulus can generate action potentials that vary significantly in terms of the count and timing. How does spiking variability originate, and does it have a functional purpose? Leveraging the Allen Institute cell types dataset, we relate the spiking reliability of cortical neurons in-vitro during the intracellular injection of current resembling synaptic inputs to their morphologic, electrophysiologic, and transcriptomic classes. Our findings demonstrate that parvalbumin+ (PV) interneurons, a subclass of inhibitory neurons, show high reliability compared to other neuronal subclasses, particularly excitatory neurons. Through computational modeling, we predict that the high reliability of PV interneurons allows for strong and precise inhibition in downstream neurons, while the lower reliability of excitatory neurons allows for integrating multiple synaptic inputs leading to a spiking rate code. These findings illuminate how spiking variability in different neuronal classes affect information propagation in the brain, leading to precise inhibition and spiking rate codes.

The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention.

Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.

Proposed Framework for Research Case Definitions of Lipedema.

Background: Our aim is to propose a framework for the development of a research case definition of lipedema, based on current available literature and those observations that can be applied to future lipedema research with the intent to standardize and strengthen the scientific evidence base. Methods and Results: We conducted a narrative review of the literature, and identified consensus characteristics and disputed characteristics that could be included in a research case definition of lipedema. After considering the strength of the evidence and how each characteristic might be measured in a research study, we recommended an approach for the development of a research case definition of lipedema that would be based on consideration of five agreed-upon characteristics, and five disputed, or less substantiated, characteristics as additional evidence to enhance specificity. Conclusions: We present a case definition framework for lipedema drawn from the scientific literature that can be applied to future studies on lipedema. Utilizing this framework should help to increase the sensitivity and specificity of case definition and provide an opportunity for meta-analysis of clinical studies and facilitate future research intercomparisons.

Genetic causes of lymphatic disorders: recent updates on the clinical and molecular aspects of lymphatic disease.

PURPOSE OF REVIEW: The lymphatic system facilitates several key functions that limit significant morbidity and mortality. Despite the impact and burden of lymphatic disorders, there are many remaining disorders whose genetic substrate remains unknown. The purpose of this review is to provide an update on the genetic causes of lymphatic disorders, while reporting on newly proposed clinical classifications of lymphatic disease. RECENT FINDINGS: We reviewed several new mutations in genes that have been identified as potential causes of lymphatic disorders including: MDFIC, EPHB 4 , and ANGPT2. Furthermore, the traditional St. George's Classification system for primary lymphatic anomalies has been updated to reflect the use of genetic testing, both as a tool for the clinical identification of lymphatic disease and as a method through which new sub-classifications of lymphatic disorders have been established within this framework. Finally, we highlighted recent clinical studies that have explored the impact of therapies such as sirolimus, ketoprofen, and acebilustat on lymphatic disorders. SUMMARY: Despite a growing body of evidence, current literature demonstrates a persistent gap in the number of known genes responsible for lymphatic disease entities. Recent clinical classification tools have been introduced in order to integrate traditional symptom- and time-based diagnostic approaches with modern genetic classifications, as highlighted in the updated St. George's classification system. With the introduction of this novel approach, clinicians may be better equipped to recognize established disease and, potentially, to identify novel causal mutations. Further research is needed to identify additional genetic causes of disease and to optimize current clinical tools for diagnosis and treatment.

Various Therapies for Lymphedema and Chronic Venous Insufficiency, Including a Multimodal At-Home Nonpneumatic Compression Treatment.

ABSTRACT: Lymphedema and chronic venous insufficiency (CVI) affect millions of people and require lifelong management. Many compression options exist for the long-term management of these conditions; however, limitations in patient mobility and adherence are common. Current options for care often present challenges with adherence because they are time-intensive and cumbersome. Innovation is needed to improve compression options for patients with chronic edematous conditions, particularly because lymphedema and CVI benefit from combination interventions. In this narrative review, the authors focus on long-term management strategies for lymphedema and CVI and highlight a nonpneumatic compression device designed for ease of use in the management of lymphedema and CVI. Using a nonpneumatic compression device that combines multiple treatment modalities demonstrates improved efficacy, quality of life, and patient adherence.

Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Pre-and post-HSCT use of TKI therapy for fusion-driven B-ALL: A case series of five pediatric, adolescent and young adult patients.

BACKGROUND: The development of tyrosine kinase inhibitors (TKIs) has significantly improved survival rates among patients with Philadelphia chromosome (Ph+) B cell acute lymphoblastic leukemia (B-ALL). Ph-like B-ALL patients lack the BCR::ABL1 translocation but share gene expression profiles with Ph+ B-ALL. The role of TKIs for Ph-like patients pre- and post-hematopoietic stem cell transplantation (HSCT) is not yet clear. CASE: Here we present five cases of pediatric, adolescent, and young adult patients who presented with Ph-like B-ALL or CML in B-ALL blast phase who were treated with personalized TKI regimens pre- and post-HSCT. CONCLUSION: This report describes several novel Ph-like fusions as well as combinations of TKIs with chemotherapy or immunotherapy not yet reported in the pediatric population. This case series provides real-world experience highlighting the potential application of pre- and post-HSCT use of TKIs in a subset of patients with targetable fusions.

Multi-Model Prediction of West Nile Virus Neuroinvasive Disease With Machine Learning for Identification of Important Regional Climatic Drivers.

West Nile virus (WNV) is the leading cause of mosquito-borne illness in the continental United States (CONUS). Spatial heterogeneity in historical incidence, environmental factors, and complex ecology make prediction of spatiotemporal variation in WNV transmission challenging. Machine learning provides promising tools for identification of important variables in such situations. To predict annual WNV neuroinvasive disease (WNND) cases in CONUS (2015-2021), we fitted 10 probabilistic models with variation in complexity from naïve to machine learning algorithm and an ensemble. We made predictions in each of nine climate regions on a hexagonal grid and evaluated each model's predictive accuracy. Using the machine learning models (random forest and neural network), we identified the relative importance and variation in ranking of predictors (historical WNND cases, climate anomalies, human demographics, and land use) across regions. We found that historical WNND cases and population density were among the most important factors while anomalies in temperature and precipitation often had relatively low importance. While the relative performance of each model varied across climatic regions, the magnitude of difference between models was small. All models except the naïve model had non-significant differences in performance relative to the baseline model (negative binomial model fit per hexagon). No model, including the ensemble or more complex machine learning models, outperformed models based on historical case counts on the hexagon or region level; these models are good forecasting benchmarks. Further work is needed to assess if predictive capacity can be improved beyond that of these historical baselines.

Effectiveness of a Nonpneumatic Active Compression Device in Older Adults with Breast Cancer-Related Lymphedema: A Subanalysis of a Randomized Crossover Trial.

Background: A recently completed clinical trial compared a novel nonpneumatic compression device (NPCD) with a traditional advanced pneumatic compression device (APCD) for the treatment of breast cancer-related lymphedema (BCRL); the study revealed that the NPCD produced superior clinical and quality-of-life (QOL) outcomes. In this subanalysis, we sought to examine these results within the subset of trial subjects aged ≥65 years. Methods: A randomized crossover head-to-head trial was conducted to compare the NPCD with a commercially available APCD. Patients were randomly assigned to one or the other device for 28 days of use, followed by a 4-week washout period before a comparable 28-day utilization of the alternate device. Limb edema, adherence to daily device use, and QOL measures were collected at day 0 and 28 of each period. Results: A total of 14 subjects were aged ≥65. During NPCD use, subjects experienced a mean decrease in limb edema of 100.3% (p = 0.0082) as well as improvements in mean overall and subscale scores of the Lymphedema Quality of Life Questionnaire (LYMQOL). By comparison, during APCD use limb edema decreased by a mean of 2.9% (p = 0.8899) with no significant changes in any LYMQOL scores. Mean adherence was significantly higher during NPCD use (96.6%) than during APCD use (58.3%, p < 0.0001). Conclusions: The novel NPCD produced superior clinical and QOL outcomes in older subjects with BCRL. ClinicalTrials.gov ID: NCT04908254.

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation.

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSIONS: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.

Life-Limiting Peripheral Organ Dysfunction in Feline Sandhoff Disease Emerges after Effective CNS Gene Therapy.

OBJECTIVE: GM2 gangliosidosis is usually fatal by 5 years of age in its 2 major subtypes, Tay-Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi-vegetative state. This study seeks to further develop adeno-associated virus (AAV) gene therapy for human translation. METHODS: Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline ß-N-acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis. RESULTS: Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4 ± 0.6 months, AAV-treated cats lived to 19.1 ± 8.6 months, and 3 of 9 cats lived >21 months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated. INTERPRETATION: The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole-body targeting will be an important consideration in next-generation approaches. ANN NEUROL 2023;94:969-986.

Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation.

BACKGROUND: Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies. METHODS: Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1 -deficient ( S1pr1 LECKO ) mice were generated. Disease progression was quantified by tail-volumetric and -histopathological measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then co-cultured with CD4 T cells, followed by an analysis of CD4 T cell activation and pathway signaling. Finally, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T cell activation. RESULTS: Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T cell infiltration in mouse lymphedema. LECs, isolated from S1pr1 LECKO mice and co-cultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs (HDLECs) promoted T helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. HDLECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro , P-selectin blockade reduced the activation and differentiation of Th cells co-cultured with sh S1PR1 -treated HDLECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSION: This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition. Clinical Perspective: What is New?: Lymphatic-specific S1pr1 deletion exacerbates lymphatic vessel malfunction and Th1/Th2 immune responses during lymphedema pathogenesis. S1pr1 -deficient LECs directly induce Th1/Th2 cell differentiation and decrease anti-inflammatory Treg populations. Peripheral dermal LECs affect CD4 T cell immune responses through direct cell contact.LEC P-selectin, regulated by S1PR1 signaling, affects CD4 T cell activation and differentiation.P-selectin blockade improves lymphedema tail swelling and decreases Th1/Th2 population in the diseased skin.What Are the Clinical Implications?: S1P/S1PR1 signaling in LECs regulates inflammation in lymphedema tissue.S1PR1 expression levels on LECs may be a useful biomarker for assessing predisposition to lymphatic disease, such as at-risk women undergoing mastectomyP-selectin Inhibitors may be effective for certain forms of lymphedema.

Development of a rat model of lymphedema and the implantation of a collagen-based medical device for therapeutic intervention.

Secondary lymphedema is a common condition among cancer survivors, and treatment strategies to prevent or treat lymphedema are in high demand. The development of novel strategies to diagnose or treat lymphedema would benefit from a robust experimental animal model of secondary lymphedema. The purpose of this methods paper is to describe and summarize our experience in developing and characterizing a rat hindlimb model of lymphedema. Here we describe a protocol to induce secondary lymphedema that takes advantage of micro computed tomography imaging for limb volume measurements and visualization of lymph drainage with near infrared imaging. To demonstrate the utility of this preclinical model for studying the therapeutic benefit of novel devices, we apply this animal model to test the efficacy of a biomaterials-based implantable medical device.