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Open research questions in Lymphatic System and Diseases

32 unresolved questions extracted from the limitations and future-work sections of 183 Lymphatic System and Diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • By integrating these understudied endothelial, lymphatic, and neural components into the broader framework of valve biology, this review highlights critical gaps in current understanding and underscores the potential of these systems as sources of early biomarkers, mechanistic insights, and therapeutic targets for next-generation valve repair and tissue engineering strategies.

    Active endothelial and neural regulation of valve biology, health, and disease · 2026 · DOI

  • Although developmental and homeostatic functions of these systems are increasingly recognized, their roles in pathological settings such as calcific aortic valve disease (CAVD) remain poorly defined.

    Active endothelial and neural regulation of valve biology, health, and disease · 2026 · DOI

  • Although vascularized lymph node transfer(VLNT) has emerged as a promising option for refractory cases, existing evidence is limited by small sample size and inconclusive results.

    Vascularized Lymph Node Transfer For Lower Extremity Lymphedema: A Systematic Review And Meta-analysis · 2026 · DOI

  • Lymph node metastasis (LNM) is a pivotal determinant of poor prognosis in ovarian cancer (OC), yet how tumor-intrinsic programs remodel the microenvironment to enable spread remains unclear.

    MEOX1 Coordinates Autocrine‐Paracrine Programs via SPHK1/S1P to Promote Lymph Node Metastasis in Ovarian Cancer · 2026 · DOI

  • PURPOSE: Lymphovenous bypass (LVB) is a well-established microsurgical treatment for secondary lymphedema, yet the optimal anatomical site for anastomosis remains unclear.

    Regional Effects Of Forearm Lymphovenous Bypass: A Prospective Analysis Of Distal And Proximal Volume Changes · 2026 · DOI

  • Although our results showed statistically signif icant improvements in shoulder ROM and in QuickDASH scores, applicabil- ity of these findings may be limited by the short duration of the study. As such, our findings and results may not be generalizable to other popula- tions or settings.

    Evaluation of The Spurgeon Method® as a Manual Therapy Protocol to Improve Shoulder Range of Motion and Function for Postmastectomy Patients · 2026 · DOI

  • • BMI below 18.5 (Underweight) • BMI 18.5–24.9 (Normal weight) • BMI 25.0–29.9 (Pre-obesity) • BMI 30.0–34.9 (Obesity class I) • BMI 35.0–39.9 (Obesity class II) • BMI above 40 (Obesity class III) • BMI should not be used as an indicator for dietitian referral 4. Do you have experience using Picture Your Plate as a nutritional questionnaire or screening instrument for patients with lymphedema? • Yes • No 5. If yes, please rate the usefulness of Picture Your Plate as a nutritional questionnaire or screening instrument for patients with lymphedema: • Not effective • Somewhat effective • Moderately effective • Very effective • Not applicable 6. If you are not currently using Picture Your Plate, after reviewing the tool (see Attachment A- pink paper), do you think it would be applicable for use in your clinical practice as a nutritional questionnaire or screening instrument for patients with lymphedema? • Yes • No 7. If you answered "No" to the previous question, why? (Mark all that apply) • Time consuming • Not within my scope of practice • Lack of training on using Picture Your Plate in clinical practice • Other: _________________ 8. Picture Your Plate™ offers interim guidance for interpreting scores (see Attachment B-blue paper). In your professional opinion, what Picture Your Plate™ score should trigger a referral from a lymphedema clinician to a dietitian for patients with lymphedema? • Picture Your Plate™ score below 40 (unhealthy dietary patterns with much room for improvement) • Picture Your Plate™ score 41-50 (unhealthy dietary pattern with much room for improvement) • Picture Your Plate™ score 51-60 (healthier dietary pattern with some room for improvement) • Picture Your Plate™ score greater than 60 (healthy dietary pattern that may have some specific eating behaviors that could be improved) 9. Are you currently using different nutritional assessment instruments for patients with lymphedema? • No • Yes 10. If yes, what nutritional assessment instruments are you currently using for patients with lymphedema? 11. Which outcome measures do you use frequently during your initial evaluation for patients with lymphedema, circle all that apply? • 30 seconds sit to stand • 6-minute walk test • Timed Up and Go • Five times sit-stand • Lower Extremity Functional Scale • Other 12. Which outcome measures in your professional do you think negatively correlate with greater BMI, circle all that apply? • 30 seconds sit to stand • 6-minute walk test • Timed Up and Go • Five times sit stand • Lower Extremity Functional Scale • Other THIS PROJECT HAS BEEN REVIEWED BY THE UNIVERSITY OF ST.

    Clinical utility of Picture Your Plate™ as a nutrition screening tool in lymphedema practice: a cross-sectional survey of certified lymphedema therapists, an exploratory study · 2026 · DOI

  • This study has several limitations. First, the single-cell data were derived from a limited number of samples (5 SL vs. 4 controls). Although we validated key findings through in vitro experiments, future studies with larger sample sizes are needed to enhance statistical power. Second, functional validation of PRKCB was limited to mRNA levels and cellular phenotypes; protein levels and kinase activity were not examined, nor were siRNA or CRISPR knockdown experiments performed to establish causality. Third, the LBT extract used was a crude extract. Although molecular docking suggested that multiple components may target PRKCB, which specific component plays a dominant role in vivo remains to be further isolated and identified. In addition, no in vivo animal experiments were conducted in this study; the therapeutic efficacy of LBT on SL and the in vivo regulatory role of PRKCB still need to be validated in animal models. Based on the findings of this study, future research can be pursued in the following directions: (1) using PRKCB-specific inhibitors or LEC-specific PRKCB knockout mice to validate the causal role of PRKCB in the pathogenesis of lymphedema; (2) isolating and purifying the active monomeric components of LBT (e.g., Tiliroside) and verifying their direct binding to PRKCB using techniques such as surface plasmon resonance (SPR); (3) establishing a mouse tail lymphedema model to evaluate the in vivo efficacy and safety of LBT extract or its monomeric components; and (4) employing phosphoproteomics technology to map the downstream signaling network of PRKCB, thereby further elucidating the molecular mechanisms by which PRKCB regulates the inflammation-metabolism crosstalk in LECs.

    Liubao tea as a functional fermented food: multi-omics insights into its modulation of lymphatic endothelial cell metabolism · 2026 · DOI

  • The persistent healthcare burden presented by BCRL represents a source of significant concern. The current standards of care in the diagnosis and treatment of breast cancer continue to pose a risk of post-treatment lymphatic disruption.

    Comprehensive overview of management and risk assessment of breast cancer-related lymphedema: a multidisciplinary approach · 2026 · DOI

  • The current narrative review is not without limitations. As with any narrative review, there is inherent bias in the selection of articles included in the manuscript (114). In order to mitigate this bias, the authors queried the PubMed, Embase, and SCOPUS databases using a Boolean search string including keywords such as “breast cancer,” “lymphedema,” “management,” and “treatment.” Included articles were published from database inception to October 2025, with a particular emphasis placed on selection of articles from the last five years (2020–2025). Articles were included if they discussed management, incidence, or otherwise furthered the reader’s current understanding of breast cancer-related lymphedema. Exclusion criteria was at the authors’ discretion as to whether the article addressed the main purpose of the present review. Particular emphasis was placed on inclusion of higher level of evidence articles (Randomized controlled trials (RCTs), prospective comparative studies, and meta-analyses). Future studies should strive to adopt a systematic format in addressing outcomes of particular manage- ment modalities for breast cancer-related lymphedema; however, the present study serves as a comprehensive and highly-descriptive review of our current understanding of these modalities.

    Comprehensive overview of management and risk assessment of breast cancer-related lymphedema: a multidisciplinary approach · 2026 · DOI

  • Improves pain, function, emotional well-being, and coping when integrated with physical therapy (88, 91– 93) Improves limb size, infection burden, and long-term functional outcomes (97, 98, 100, 101) Requires ongoing adherence to therapy and compression (78, 88) Long-lasting volume reduction; lifelong compression often required after excisional surgery (15) Limited effectiveness in advanced disease; high patient burden and need for sustained adherence (78, 89) Requires specialized expertise, operative resources, and individualized planning (94, 99, 101) HRQOL, health-related quality of life; BCRL, breast cancer-related lymphedema; CDT, Complex Decongestive Therapy; MLD, Manual lymphatic drainage; IPC, Intermittent pneumatic compression; LVA, Lymphaticovenous anastomosis; VLNT, Vascularized lymph node transfer. administration of ADSC-derived extracellular vesicles (EVs) was associated with reduced limb swelling and increased capillary and lymphatic vessel density, supporting a proposed paracrine, cell-free contribution to lymphatic repair (102). Together, these findings suggest that stem cell-based regenerative strategies may promote lymphatic regeneration in preclinical models. However, the evi- dence remains largely limited to animal studies and early-phase clinical data. These approaches therefore remain experimental and require validation in large-scale, controlled trials prior to clini- cal application. FIGURE 4 Schematic representation of mesenchymal stem cell-based regenerative approach in breast cancer-related lymphedema (BCRL).

    Comprehensive overview of management and risk assessment of breast cancer-related lymphedema: a multidisciplinary approach · 2026 · DOI

  • This narrative review has several limitations. The available studies are heterogeneous in diagnostic criteria, study design, and cohort selection, which may influence the comparability of reported findings. Most cohorts derive from specialized referral centers and rely largely on observational data, and in some cases self-reported information, potentially introducing selection bias and confounding factors. In addition, the present analysis represents a narrative synthesis rather than a systematic review or meta-analysis and therefore cannot quantify the strength of associations between lipedema and the conditions described. Consequently, the systemic interpretative framework proposed here should be considered hypothesis-generating and requires confirmation through prospective and mechanistic studies.

    Comorbidities in lipedema: toward a systemic perspective – a narrative review · 2026 · DOI

  • Future studies should determine whether enhancing lymphatic flow with LPT can be translated clinically and whether this approach maintains therapeutic benefit in human metastatic disease.

    Lymphatic pumping technique in mice alters blood parameters and metastatic melanoma in an age-dependent manner · 2026 · DOI

  • The assumed effect of lymphangiogenesis induced by LPT in middle-aged mice receiving immunotherapy was not directly measured, limiting understanding of LPT-immunotherapy interactions in this age group.

    Lymphatic pumping technique in mice alters blood parameters and metastatic melanoma in an age-dependent manner · 2026 · DOI

  • The mechanism underlying why LPT did not increase blood parameters in middle-aged animals remains unclear; it could be either that their extravascular reserve of blood components is lower, or that increased tissue stiffness reduces LPT's ability to flux cells.

    Lymphatic pumping technique in mice alters blood parameters and metastatic melanoma in an age-dependent manner · 2026 · DOI

  • The therapeutic potential of photobiomodulation (PBM) for lymphoedema has been demonstrated by various studies, but the existing literature is limited by the lack of rigorous and consistent high-level evidence to allow for conclusive recommendations.

    Modelling and Quantifying The Impact of Photobiomodulation (PBM) on Biological Processes Relevant to Lymphangiogenesis, Anti-Inflammation, and Tissue Regeneration Processes: Results from a Meta-Analysis and a Neural Network Modelling · 2024 · DOI

  • Epidemiological burden estimates for lymphedema vary widely across populations, and standardized diagnostic criteria for lymphedema classification across primary, secondary, and hereditary forms remain inconsistently applied in prevalence studies; prospective cohort studies with uniform measurement protocols are needed.

    Biology of Lymphedema · 2021 · DOI

  • The influence of local hyperthermia on lymphedematous skin has been documented in single studies (ref. 37), but the mechanisms by which temperature affects lymphatic clearance and tissue hyaluronan accumulation have not been systematically investigated across varying thermal regimens and lymphedema stages.

    Biology of Lymphedema · 2021 · DOI

  • Genetic risk factors for secondary lymphedema have been primarily studied in European and Italian cohorts (refs. 61); epidemiological and genetic characterization in African breast cancer populations remains insufficient to establish population-specific risk profiles and prevalence estimates.

    Biology of Lymphedema · 2021 · DOI

  • Genetic predisposition to secondary lymphedema after breast cancer has been suggested (refs. 59-60), but specific genetic variants beyond CELSR1, VEGFR-3, and FOXC2 mutations remain unidentified; comprehensive genome-wide association studies in diverse cancer populations are required to characterize inherited susceptibility mechanisms.

    Biology of Lymphedema · 2021 · DOI

  • Physical therapy effects on hyaluronan clearance and volume-regulating hormones in lower limb lymphedema patients have only been assessed in a pilot study (ref. 35); larger randomized controlled trials with standardized physical therapy protocols and extended follow-up periods are needed to establish clinical efficacy.

    Biology of Lymphedema · 2021 · DOI

  • The current standard management for any type of lymphedema includes multi-layered short strech bandaging, manual lymphatic drainage (MLD), use of compression garment(s) and education, but there is no standard therapy protocol is available for head and neck lymphedema (HNL).

    Kinesio Taping in Head and Neck Cancer Related Lymphedema · 2018 · DOI

  • The post-exercise decrease of plasma hyaluronan has been documented, but the underlying mechanism remains unclear—whether this reflects increased clearance versus diminished production needs to be resolved through differential kinetic studies measuring hyaluronan synthesis and degradation rates simultaneously.

    Biology of Lymphedema · 2021 · DOI

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32 open questions have been extracted from the limitations and future-work passages of 183 Lymphatic System and Diseases papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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