Efficacy of Immediate Lymphatic Reconstruction to Decrease Incidence of Breast Cancer-related Lymphedema: Preliminary Results of Randomized Controlled Trial.

OBJECTIVE: To conduct a randomized controlled trial (RCT) on the efficacy of immediate lymphatic reconstruction (ILR) for decreasing the incidence of breast cancer-related lymphedema (BCRL) after axillary lymph node dissection (ALND). BACKGROUND: Despite encouraging results in small studies, an appropriately powered RCT on ILR has not been performed. METHODS: Women undergoing ALND for breast cancer were randomized in the operating room 1:1 to either ILR, if technically feasible, or no ILR (control). The ILR group underwent lymphatic anastomosis to a regional vein using microsurgical techniques; control group had no repair and cut lymphatics were ligated. Relative volume change (RVC), bioimpedance, quality of life (QoL), and compression use were evaluated at baseline and every 6 months postoperatively up to 24 months. Indocyanine green (ICG) lymphography was performed at baseline and 12 and 24 months postoperatively. The primary outcome was the incidence of BCRL, defined as ≥10% RVC from baseline in the affected extremity at 12-, 18-, or 24-month follow-up. RESULTS: Of 72 patients randomized to ILR and 72 to control from January 2020 to March 2023, our preliminary analysis includes 99 patients with 12-month follow-up, 70 with 18-month follow-up, and 40 with 24-month follow-up. The cumulative incidence of BCRL was 9.5% in the ILR group and 32% in the control group ( P =0.014). The ILR group had lower bioimpedance values, decreased compression usage, better lymphatic function on ICG lymphography, and better QoL than the control group. CONCLUSIONS: Preliminary results of our RCT show that ILR after ALND decreases BCRL incidence. Our goal is to finish the accrual of 174 patients with 24-month follow-up.

A Prospective Study on the Safety and Efficacy of Vascularized Lymph Node Transplant.

PURPOSE: While vascularized lymph node transplant (VLNT) has gained popularity, there are a lack of prospective long-term studies and standardized outcomes. The purpose of this study was to evaluate the safety and efficacy of VLNT using all available outcome measures. METHODS: This was a prospective study on all consecutive patients who underwent VLNT. Outcomes were assessed with 2 patient-reported outcome metrics, limb volume, bioimpedance, need for compression, and incidence of cellulitis. RESULTS: There were 89 patients with the following donor sites: omentum (73%), axilla (13%), supraclavicular (7%), groin (3.5%). The mean follow-up was 23.7±12 months. There was a significant improvement at 2 years postoperatively across all outcome measures: 28.4% improvement in the Lymphedema Life Impact Scale, 20% average reduction in limb volume, 27.5% improvement in bioimpedance score, 93% reduction in cellulitis, and 34% of patients no longer required compression. Complications were transient and low without any donor site lymphedema. CONCLUSIONS: VLNT is a safe and effective treatment for lymphedema with significant benefits fully manifesting at 2 years postoperatively. Omentum does not have any donor site lymphedema risk making it an attractive first choice.

Appropriateness of Computed Tomography Scanning in the Diagnosis of Craniosynostosis.

INTRODUCTION: Although physicians from a variety of specialties encounter infants with possible craniosynostosis, judicious use of computed tomography (CT) imaging is important to avoid unnecessary radiation exposure and healthcare expense. The present study seeks to determine whether differences in specialty of ordering physician affects frequency of resulting diagnostic confirmations requiring operative intervention. METHODS: Radiology databases from 2 institutions were queried for CT reports or indications that included "craniosynostosis" or "plagiocephaly." Patient demographics, specialty of ordering physician, confirmed diagnosis, and operative interventions were recorded. Cost analysis was performed using the fixed unit cost for a head CT to calculate the expense before 1 study led to operative intervention. RESULTS: Three hundred eighty-two patients were included. 184 (48.2%) CT scans were ordered by craniofacial surgeons, 71 (18.6%) were ordered by neurosurgeons, and 127 (33.3%) were ordered by pediatricians. One hundred four (27.2%) patients received a diagnosis of craniosynostosis requiring operative intervention. Craniofacial surgeons and neurosurgeons were more likely than pediatricians to order CT scans that resulted in a diagnosis of craniosynostosis requiring operative intervention (P < 0.001), with no difference between craniofacial surgeons and neurosurgeons (P = 1.0). The estimated cost of obtaining an impact CT scan when ordered by neurosurgeons or craniofacial surgeons as compared to pediatricians was $2369.69 versus $13,493.75. CONCLUSIONS: Clinicians who more frequently encounter craniosynostosis (craniofacial and neurosurgeons) had a higher likelihood of ordering CT images that resulted in a diagnosis of craniosynostosis requiring operative intervention. This study should prompt multi-disciplinary interventions aimed at improving evaluation of pretest probability before CT imaging.

Lymphatics in Tumor Progression and Immunomodulation.

The lymphatic system consists of a unidirectional hierarchy of vessels responsible for fluid homeostasis, lipid absorption, and the transport of immune cells and antigens to secondary lymphoid organs. In cancer, lymphatics play complex and heterogenous roles that can promote or inhibit tumor growth. While lymphatic proliferation and remodeling promote tumor dissemination, functional lymphatics are necessary for generating an effective immune response. Recent reports have noted lymphatic-dependent effects on the efficacy of immunotherapy. These findings suggest that the impact of lymphatic vessels on tumor progression is organ- and context-specific and that a greater understanding of the interaction of tumor cells, lymphatics, and the tumor microenvironment can unveil novel therapies.

The Role of Precedex in Post-Operative Pain Management Following Craniosynostosis Repair.

The application of dexmedetomidine (precedex) in pediatric settings has increased due to its superior safety and efficacy profile and it has been specifically suggested as an adjunct to IV acetaminophen and a substitute for morphine in craniosynostosis repair. However, reports of its use in pediatrics, let alone in craniosynostosis repair, remain limited and to date there are no studies addressing its use after craniosynostosis repair in children. This study is an IRB-approved retrospective case review of the use of dexmedetomidine following pediatric craniosynostosis repair as a postoperative analgesic/sedative agent at one institution.

Postoperative Pain Management Following Craniosynostosis Repair: Current Practices and Future Directions.

BACKGROUND: Postoperative analgesia following craniosynostosis repair is a clinical challenge for plastic and reconstructive surgeons. There is a paucity of published data on the postoperative pain associated with craniosynostosis repair procedures and the prescribed analgesia varies with different unit protocols. The authors sought to summarize the current knowledge of the postoperative analgesia following craniosynostosis repair by reviewing the literature for existing regimens, clinical outcomes, and recommendations. METHODS: Two independent investigators conducted a literature search of the Pubmed, Cochrane, and Google Scholar databases for relevant clinical studies. Studies were abstracted for procedure type, postoperative pain management protocol, pain scores, side effects, complications, and clinical recommendations. RESULTS: Ten studies describing the use of analgesic agents in open craniosynostosis surgery from 2000 to 2018 were fully reviewed, comprising a total of 431 patients undergoing surgical procedures using a combination regimen of narcotic and nonnarcotic agents (n = 315) and nonnarcotic agents alone (n = 116). CONCLUSION: Multimodal analgesia is the primary regimen used following open craniosynostosis repair procedures. Opioids are a critical component in pain management regimens, relieving patient discomfort. However, due to the deleterious effects that come with their prolonged use, intravenous acetaminophen is currently used as an alternative in many centers. The preferred mode of pain medication administration in the pediatric population is increasingly via the intravenous route which ensures that a full dose of pain medication is given. The authors suggest the use of dexmedetomidine, both an adjunct to intravenous acetaminophen and as a substitute for morphine due to its superior safety and efficacy profile.

Vitamin D and rheumatoid arthritis: an ongoing mystery.

PURPOSE OF REVIEW: In recent years, there has been a growing interest in the value of vitamin D and its effects on autoimmunity. The aim of this review is to summarize the current knowledge on the association between vitamin D and rheumatoid arthritis (RA) in terms of prevalence, disease activity, clinical expression, serology and gene polymorphisms of vitamin D receptors. RECENT FINDINGS: Studies have shown contrasting findings concerning the association between vitamin D levels and RA. Vitamin D seems to have immunomodulatory properties. Therefore, low vitamin D levels could contribute to increased immune activation. However, the potential role of vitamin D supplementation in preventing RA manifestation and its beneficial role as a component of RA treatment remain controversial. The relationship between RA susceptibility and vitamin D polymorphisms is also unclear. SUMMARY: Despite advancements synthesized by some recent meta-analyses, the relationship between vitamin D and RA requires further evaluation. Further research is needed to confirm the relationship between RA susceptibility and vitamin D polymorphisms and to determine whether vitamin D plays a role in preventing the manifestation of RA. Finally, additional studies are required to determine the impact and optimal amount of vitamin D supplementation in the treatment of RA patients.

Clinical Applications of Tranexamic Acid (TXA) in Plastic and Reconstructive Surgery.

PURPOSE: Tranexamic Acid (TXA) has gained increasing recognition as a valuable pharmacologic agent within plastic surgery. This study reviews the scientific evidence regarding the use of TXA in the full range of plastic and reconstructive surgery to provide clinical recommendations regarding for safe and effective use in various plastic surgical procedures. METHODS: A systematic review and meta-analysis were conducted following the PRISMA guidelines. An established appraisal process was used to rate the quality of articles (Grading of Recommendations Assessment, Development, and Evaluation methodology). RESULTS: Forty-five studies describing the use of TXA in plastic surgery were included. There is moderate-certainty evidence to support the use of intravenous administration of TXA in craniofacial surgery procedures to reduce blood-loss and transfusion requirements. There is high-certainty evidence to support the use of TXA in cosmetic surgery and intravenous administration in rhinoplasty procedures to reduce blood-loss. Further high-level studies are needed to determine TXA's effects on hematoma rates in facelift surgery and breast-related procedures. There is moderate-certainty evidence to support the use of TXA in burn care. Further studies are required to provide quantitative conclusions on the effects of TXA administration in microsurgery. CONCLUSIONS: This is the largest study to date on the use of TXA in plastic surgery and the first to provide clinical recommendations. The literature highlights TXA's promising role in the fields of craniofacial surgery, cosmetic surgery and burn care. Standardized, objective measurements are required to provide quantitative conclusions regarding TXAs effects on ecchymoses and edema in cosmetic surgery procedures.

GLP-1 receptor agonist as an effective treatment for breast cancer-related lymphedema: a case report.

Introduction: Lymphedema is a major public health issue for many women undergoing breast cancer treatment. Although weight loss has been reported to be beneficial in the treatment of lymphedema, no studies to date have examined the use of GLP-1RAs for the treatment of secondary lymphedema. This case report describes a patient who experienced significant resolution of her breast cancer-related lymphedema after initiation of a GLP-1RA for weight loss. Main symptoms and/or important clinical findings: Nine months postoperatively the patient developed arm swelling and disability. While on adjuvant chemo and hormonal therapy, her weight increased dramatically and peaked 4 years later. Corresponding to her weight gain was significant worsening of her symptoms. The main diagnoses therapeutic interventions and outcomes: Due to adjuvant cancer-related weight gain and inability to lose weight with diet and exercise, she was referred for evaluation and diagnosed with lymphedema. The patient started treatment with a Glucagon-like peptide 1 receptor agonist and lost 24% of her body weight over the next 13 months. The improvement in her lymphedema mirrored her weight loss. Her limb volume difference dropped from 10.3% down to 3.4% and she no longer required a compression garment. Her imaging demonstrated return of lymphatic pumping and she experienced a significant improvement in quality of life, assessed by a validated lymphedema-specific patient reported outcome (PROM). She remains on hormonal therapy, no longer needs compression and is back to regular exercise without impairment. Conclusions: GLP-1 RAs provide a potential medical option for many patients struggling with weight gain and lymphedema. We have observed by all objective measures a significant reduction in lymphedema and the elimination of compression in the case presented as a direct result of GLP-1 RA. This may also reduce a patient's BMI to the point where they become a good candidate for lymphovenous bypass or vascularized lymph node transplant when indicated.

Immediate Lymphatic Reconstruction with Vascularized Omentum Lymph Node Transplant: Reducing the Risk of Both Painful Contracture and Lymphedema.

Patients undergoing extensive lymph node dissection and radiation are at high risk for not only lymphedema but also painful contracture. In a standard lymphadenectomy, immediate lymphatic reconstruction using a lymphovenous bypass is effective in reconstructing the lymphatic defect. However, a more aggressive nodal clearance leaves the patient with a large cavity and skeletonized neurovascular structures, often resulting in severe contracture, pain, cosmetic deformity, and venous stricture. Adjuvant radiotherapy to the nodal bed can lead to severe and permanent disability despite physical therapy. Typically, these patients are referred to us after the fact, where surgery will rarely restore the patient to normal function. In an effort to avoid lymphedema and contracture, we have been reconstructing both the lymphatic and soft tissue defect during lymphadenectomy, using vascularized omentum lymphatic transplant (VOLT). A total of 13 patients underwent immediate reconstruction with VOLT at the time of axillary (n = 8; 61.5%) or groin (n = 5; 38.5%) dissection. No postoperative complications were observed. The mean follow-up time was 15.1 ±â€…12.5 months. Only one lower extremity patient developed mild lymphedema (11% volume differential), with excellent scores in validated patient-reported outcomes. All patients maintained full range of motion with no pain. None of the 13 patients required a compression garment. Immediate lymphatic reconstruction with VOLT is a promising procedure for minimizing the risk of lymphedema and contracture in the highest risk patients undergoing particularly extensive lymph node dissection and radiotherapy.

Breast Cancer-Related Lymphedema Results in Impaired Epidermal Differentiation and Tight Junction Dysfunction.

Breast cancer-related lymphedema (BCRL) is characterized by skin changes, swelling, fibrosis, and recurrent skin infections. Clinical studies have suggested that lymphedema results in skin barrier defects; however, the underlying cellular mechanisms and the effects of bacterial contamination on skin barrier function remain unknown. In matched biopsies from patients with unilateral BCRL, we observed decreased expression of FLG and the tight junction protein ZO-1 in skin affected by moderate lymphedema or by subclinical lymphedema in which dermal backflow of lymph was identified by indocyanine green lymphography, relative to those in the controls (areas without backflow and from the unaffected arm). In vitro stimulation of keratinocytes with lymph fluid obtained from patients undergoing lymphedema surgery led to the same changes as well as increased expression of keratin 14, a marker of immature keratinocytes. Finally, using mouse models of lymphedema, we showed that similar to the clinical scenario, the expression of skin barrier proteins was decreased relative to that in normal skin and that colonization with Staphylococcus epidermidis bacteria amplified this effect as well as lymphedema severity. Taken together, our findings suggest that lymphatic fluid stasis contributes to skin barrier dysfunction in lymphedema.

The Vicious Circle of Stasis, Inflammation, and Fibrosis in Lymphedema.

SUMMARY: Lymphedema is a progressive disease of the lymphatic system arising from impaired lymphatic drainage, accumulation of interstitial fluid, and fibroadipose deposition. Secondary lymphedema resulting from cancer treatment is the most common form of the disease in developed countries, affecting 15% to 40% of patients with breast cancer after lymph node dissection. Despite recent advances in microsurgery, outcomes remain variable and, in some cases, inadequate. Thus, development of novel treatment strategies is an important goal. Research over the past decade suggests that lymphatic injury initiates a chronic inflammatory response that regulates the pathophysiology of lymphedema. T-cell inflammation plays a key role in this response. In this review, the authors highlight the cellular and molecular mechanisms of lymphedema and discuss promising preclinical therapies.

Topical captopril: a promising treatment for secondary lymphedema.

Transforming growth factor-beta 1 (TGF-ß1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-ß1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-ß1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. Therefore, we analyzed the expression of ACE and Ang II in clinical lymphedema biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and mouse models, and found that cutaneous ACE expression is increased in lymphedematous tissues. Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-ß1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.

The Future of Lymphedema: Potential Therapeutic Targets for Treatment.

Purpose of Review: This review aims to summarize the current knowledge regarding the pharmacological interventions studied in both experimental and clinical trials for secondary lymphedema. Recent Findings: Lymphedema is a progressive disease that results in tissue swelling, pain, and functional disability. The most common cause of secondary lymphedema in developed countries is an iatrogenic injury to the lymphatic system during cancer treatment. Despite its high incidence and severe sequelae, lymphedema is usually treated with palliative options such as compression and physical therapy. However, recent studies on the pathophysiology of lymphedema have explored pharmacological treatments in preclinical and early phase clinical trials. Summary: Many potential treatment options for lymphedema have been explored throughout the past two decades including systemic agents and topical approaches to decrease the potential toxicity of systemic treatment. Treatment strategies including lymphangiogenic factors, anti-inflammatory agents, and anti-fibrotic therapies may be used independently or in conjunction with surgical approaches.

Skin microbiome alterations in upper extremity secondary lymphedema.

Lymphedema is a chronic condition that commonly occur from lymphatic injury following surgical resection of solid malignancies. While many studies have centered on the molecular and immune pathways that perpetuate lymphatic dysfunction, the role of the skin microbiome in lymphedema development remains unclear. In this study, skin swabs collected from normal and lymphedema forearms of 30 patients with unilateral upper extremity lymphedema were analyzed by 16S ribosomal RNA sequencing. Statistical models for microbiome data were utilized to correlate clinical variables with microbial profiles. Overall, 872 bacterial taxa were identified. There were no significant differences in microbial alpha diversity of the colonizing bacteria between normal and lymphedema skin samples (p = 0.25). Notably, for patients without a history of infection, a one-fold change in relative limb volume was significantly associated with a 0.58-unit increase in Bray-Curtis microbial distance between paired limbs (95%CI = 0.11,1.05, p = 0.02). Additionally, several genera, including Propionibacterium and Streptococcus, demonstrated high variability between paired samples. In summary, we demonstrate high compositional heterogeneity in the skin microbiome in upper extremity secondary lymphedema, supporting future studies into the role of host-microbe interactions on lymphedema pathophysiology.

Dysregulation of Lymphatic Endothelial VEGFR3 Signaling in Disease.

Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3), a receptor tyrosine kinase encoded by the FLT4 gene, plays a significant role in the morphogenesis and maintenance of lymphatic vessels. Under both normal and pathologic conditions, VEGF-C and VEGF-D bind VEGFR3 on the surface of lymphatic endothelial cells (LECs) and induce lymphatic proliferation, migration, and survival by activating intracellular PI3K-Akt and MAPK-ERK signaling pathways. Impaired lymphatic function and VEGFR3 signaling has been linked with a myriad of commonly encountered clinical conditions. This review provides a brief overview of intracellular VEGFR3 signaling in LECs and explores examples of dysregulated VEGFR3 signaling in various disease states, including (1) lymphedema, (2) tumor growth and metastasis, (3) obesity and metabolic syndrome, (4) organ transplant rejection, and (5) autoimmune disorders. A more complete understanding of the molecular mechanisms underlying the lymphatic pathology of each disease will allow for the development of novel strategies to treat these chronic and often debilitating illnesses.

Doxycycline for the treatment of breast cancer-related lymphedema.

Purpose: Secondary lymphedema is a common complication of cancer treatment for which no effective drug treatments yet exist. Level I clinical data suggests that doxycycline is effective for treating filariasis-induced lymphedema, in which it decreases tissue edema and skin abnormalities; however, this treatment has not been tested for cancer-related lymphedema. Over the past year, we used doxycycline in an off-label manner in patients with breast cancer-related secondary lymphedema. The purpose of this report was to retrospectively analyze the efficacy of this treatment. Methods: Patients who presented to our lymphedema clinic between January 2021 and January 2022 were evaluated, and barring allergies or contraindications to doxycycline treatment, were counseled on the off-label use of this treatment. Patients who wished to proceed were treated with doxycycline (200 mg given orally once daily) for 6 weeks. After IRB approval of this study, lymphedema outcomes were retrospectively reviewed. Results: Seventeen patients with a mean follow-up of 17.0 ± 13.2 weeks were identified in our retrospective review. Although doxycycline treatment had no significant effect on relative limb volume change or L-Dex scores, we found a significant improvement in patient-reported quality of life. Analysis of patient responses to the Lymphedema Life Impact Scale showed a significant improvement in the total impairment score due to improvements in the physical and psychological well-being subscales (p = 0.03, p = 0.03, p = 0.04, respectively). Conclusion: This small, retrospective study did not show significant improvements in limb volume or L-Dex scores in patients with breast cancer-related lymphedema treated with doxycycline. However, our patients reported improvements in quality-of-life measures using a validated lymphedema patient-reported outcome instrument. Our results suggest that doxycycline may be of use in patients with breast cancer-related lymphedema; however, larger and more rigorous studies are needed.

Pharmacological Treatment of Secondary Lymphedema.

Lymphedema is a chronic disease that results in swelling and decreased function due to abnormal lymphatic fluid clearance and chronic inflammation. In Western countries, lymphedema most commonly develops following an iatrogenic injury to the lymphatic system during cancer treatment. It is estimated that as many as 10 million patients suffer from lymphedema in the United States alone. Current treatments for lymphedema are palliative in nature, relying on compression garments and physical therapy to decrease interstitial fluid accumulation in the affected extremity. However, recent discoveries have increased the hopes of therapeutic interventions that may promote lymphatic regeneration and function. The purpose of this review is to summarize current experimental pharmacological strategies in the treatment of lymphedema.

Structural and Functional Changes in Aged Skin Lymphatic Vessels.

Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.