Clinical Lymphedema Research Articles

Post-operative care for patients following surgical treatment of lymphedema.

Surgical treatments are promising for the treatment of lymphedema. It is important for patients, healthcare providers, and lymphedema community to understand that surgical treatments currently are not a cure for lymphedema but have provided promising options for patients. Post-operative care for patients following surgical treatment of lymphedema is vital to optimize and sustain patient outcomes. This expert-consensus statement addresses current practice and research needs for standardized post-operative care, a core set of outcome measures, quality of care, and training of healthcare providers. Current research and clinical practice support non-surgical lymphedema therapy, also known as conservative therapy of lymphedema (e.g., compression therapy, or manual lymph drainage, or Complete Decongestive Therapy) as an essential part of post-operative care. Importantly, patient education should focus on patients' understanding that surgery is not a cure and the importance to adhere to post-operative care and life-long self-monitoring to sustain surgical results of limb volume reduction, relief of symptoms, and mitigate known or ongoing risk factors for recurrence of lymphedema. To optimize patient outcomes, it is crucial to have a multidisciplinary professional team consisting of well-qualified and credentialed healthcare providers participating in ongoing training and education. The essentials recommended by this expert-consensus are an initial and foundational step to build clinical standards for best practice and provide directions for future research.

Cross-Sectional Analysis of Patients Referred to a Tertiary Lymphatic Surgery Center.

Secondary lymphedema has become an increasingly common reason for referral to plastic surgery. Understanding referral patterns for lymphedema patients is crucial to optimizing care. Patients referred to plastic surgery for lymphedema at a lymphatic surgery center between January 2016 and 2023 were identified. Primary outcomes of interest included clinical lymphedema staging and characteristics, patient demographics, and referral sources. Secondary outcomes were prior lymphedema treatment, agreement between referring provider and plastic surgeon's diagnosis, and patient disposition after surgical evaluation. Descriptive statistics and multivariate logistic regression analysis were performed. A total of 285 patients with extremity edema were referred to plastic surgery; 60.0% of patients had prior malignancy, 45.6% of patients had undergone a prior lymph node procedure, and 40% had received radiation, while 56.8% of patients had previously seen occupational therapy. Body mass index (BMI, OR 1.09, p = 0.013), age (OR 1.25, p = 0.005), and prior physical oroccupational therapy (OR 1.23, p = 0.011) were associated with later stages of lymphedema upon presentation, while prior radiation (OR 0.79, p = 0.006) and malignancy (OR 0.85, p = 0.034) were associated with earlier stages of lymphedema. Self-referral (27.4%), primary care (17.9%), and medical oncology (14.7%) were the most common referral sources. Lymphedema was confirmed in 68.1% of referrals, and 28.5% of these patients proceeded to surgery. Patients were more likely to be operative candidates if referred by primary care (RR 2.1, p = 0.006) or occupational therapy (RR 4.6, p = 0.010). Referred patients ultimately undergo lymphedema surgery at relatively low rates, indicating that most referred patients are not ideal surgical candidates. Optimizing referral patterns through multidisciplinary education may enhance the referral process and improve access to lymphedema surgery.

Navigating Lymphedema: The Impact of Indocyanine Green Lymphography on Personalized Therapy Outcomes in Breast Cancer Patients

AimTo evaluate the role of Indocyanine Green Lymphography (ICG_L) in the early diagnosis and personalized management of breast cancer-related lymphedema (BCRL) among high-risk breast cancer (BC) survivors. MethodsPatients who admitted to the UPMC Magee-Womens Hospital Lymphedema Program between October 2018 and December 2021 with episodic symptoms were enrolled into the study. Patient demographics, clinical characteristics, and outcomes were prospectively collected and retrospectively analysed. Lymphatic flow disruptions were identified and guided personalized therapeutic interventions were guided by ICG_L. ResultsAmong 154 BC survivors, 184 arms were evaluated. Initial ICG_L showed 57.1% had no lymphedema, while 42.9% were classified as stage 1 to 3 lymphedema. Early diagnosis and personalized interventions provided improved outcomes, with only 4.3% developing clinical lymphedema after a median follow-up of 27 months. Patients exhibited stable or improved symptoms with individualized treatments such as manual lymphatic drainage, compression therapies, and physiotherapy. ConclusionICG_L evaluation is essential for patients at high-risk of developing BCRL. Early diagnosis before clinical onset of lymphedema, and ICG_L guided therapy significantly enhances the clinical outcomes and improves lymphedema management. Micro AbstractBreast cancer-related lymphedema (BCRL) is a common complication following breast cancer treatment, characterized by chronic swelling and functional impairment. This study investigates the role of indocyanine green lymphography (ICG_L) for early BCRL detection among high-risk breast cancer survivors. By identifying subclinical lymphatic disruptions, personalized physical therapy interventions are implemented, leading to improved patient outcomes. With a median follow-up of 27 months, only 4.3% of patients developed clinical BCRL, highlighting the efficacy of early diagnosis and tailored preventive strategies in managing lymphedema progression.

Addition of prophylactic compression garments to standard care to prevent irreversible lower limb lymphoedema after gynaeco-oncological therapy (Gynolymph): protocol for a randomised controlled trial embedded within an observation cohort study

IntroductionIn female patients diagnosed with gynaecological cancer, the main priority is treating cancer itself. However, a significant number of these patients develop lower limb lymphoedema (LLL), with its incidence strongly...

Abstract PO3-12-07: Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema

Abstract Background: Early detection of Breast cancer-related lymphedema (BCRL) is crucial since it can significantly reduce the negative impact on a patient’s quality of life after breast cancer treatment. Several objective screening methods have been used in prior studies but have not proven accurate due to a lack of standardization. Bioimpedance spectroscopy (BIS), which assesses tissue resistance to an electric current and converts it into a score to measure interstitial fluid content, has proven to be an accurate tool in diagnosing lymphedema. SOZO® is a BIS device that generates quantitative results in real time and provides a Lymphedema Index (L-Dex) score by measuring the patient's extracellular fluid volume. However, there is a paucity of literature highlighting its clinical applicability. Thus, we aimed to evaluate the clinical utility of SOZO® in diagnosing BCRL in patients undergoing breast cancer surgery. Materials & Methods: A retrospective chart review was carried out of patients who underwent axillary surgery from January 2019 to December 2022. Demographic information such as age, body mass index (BMI), gender, ethnicity, disease pathology, cancer stage, type of axillary surgery, neoadjuvant and adjuvant treatment received was recorded. Patients undergoing sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) were assessed for their preoperative L-Dex score, and they were followed up postoperatively with repeated measurements of their L-Dex score to diagnose lymphedema for a year at 3 months intervals. Clinical lymphedema was defined as those having an absolute L-Dex score of more than +10 and an increase in L-Dex score by 6.5 from the baseline. SOZO® scores measured at each follow-up were compared to their preoperative baseline scores. Results: A total of 200 patients’ data was evaluated whose mean age and BMI were 57.5+10.9 years and 29.6+5.6 kg/m2, respectively. Eighty-five percent of the patients belonged to ethnic minority groups. Furthermore, 84.5% (n=169) of the patients had SLNB, and 15.5% (n=31) had ALND. All the patients included in the study had their preoperative and postoperative quarterly L-Dex scores recorded. Pre- and post-operative L-Dex scores had a mean of -0.20+6.6 and 0.61+6.8, respectively. A total of 20 (10%) patients developed lymphedema without symptoms detected by SOZO®, with 19 (9.5%) resolving at their respective 3-month follow-up and 1 (0.5%) patient with persistent lymphedema at the end of the 24-month follow-up. All 20 patients were treated with a compression sleeve. Of the 20 patients with lymphedema, 4 patients underwent ALND, whereas 16 patients had SLNB. When compared to their preoperative baseline scores, all patients' SOZO® measurements had an absolute score of more than 10 and an increase of 6.5 from their baseline score. Additionally, 21 other patients had an increase in score of 6.5 from their baseline measurements but did not meet the cut-off range of an absolute score of +10. Therefore, we excluded them from the diagnosis of BCRL, and none of these patients later developed any signs of BCRL, such as swelling, pain, or discomfort. Conclusion: SOZO® procedure can accurately detect BCRL. In our study, 1 patient developed clinical lymphedema after undergoing SLNB and was diagnosed using SOZO®. Additionally, 19 patients who were initially diagnosed with lymphedema were later categorized as transient due to the resolution of lymphedema on follow-up. Early identification of transient lymphedema using SOZO® resulted in the prevention of a potentially life-long debilitation in our patients. Moreover, our findings underscore that an increase in SOZO® score from the baseline by > 6.5 with an absolute score of more than +10 should be the threshold to clinically diagnose lymphedema. Future studies with larger sample sizes and longer follow-up duration are necessary to understand better the utility of SOZO® in diagnosing BCRL. Table 1: Baseline characteristics and follow-up data of the patients included in the study. Citation Format: Fardeen Bhimani, Sheldon Feldman, Yu Chen, Anjuli Gupta, Jessica Pastoriza, Areej Shihabi, Maureen McEvoy. Utility of Volumetric Measurement for Clinical Diagnosis of Breast Cancer-Related Lymphedema [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-07.

Prediction of Overall Disease Burden in (y)pN1 Breast Cancer Using Knowledge-Based Machine Learning Model.

We aimed to construct an expert knowledge-based Bayesian network (BN) model for assessing the overall disease burden (ODB) in (y)pN1 breast cancer patients and compare ODB across arms of ongoing trials. Utilizing institutional data and expert surveys, we developed a BN model for (y)pN1 breast cancer. Expert-derived probabilities and disability weights for radiotherapy-related benefit (e.g., 7-year disease-free survival [DFS]) and toxicities were integrated into the model. ODB was defined as the sum of disability weights multiplied by probabilities. In silico predictions were conducted for Alliance A011202, PORT-N1, RAPCHEM, and RT-CHARM trials, comparing ODB, 7-year DFS, and side effects. In the Alliance A011202 trial, 7-year DFS was 80.1% in both arms. Axillary lymph node dissection led to higher clinical lymphedema and ODB compared to sentinel lymph node biopsy with full regional nodal irradiation (RNI). In the PORT-N1 trial, the control arm (whole-breast irradiation [WBI] with RNI or post-mastectomy radiotherapy [PMRT]) had an ODB of 0.254, while the experimental arm (WBI alone or no PMRT) had an ODB of 0.255. In the RAPCHEM trial, the radiotherapy field did not impact the 7-year DFS in ypN1 patients. However, there was a mild ODB increase with a larger irradiation field. In the RT-CHARM trial, we identified factors associated with the major complication rate, which ranged from 18.3% to 22.1%. The expert knowledge-based BN model predicted ongoing trial outcomes, validating reported results and assumptions. In addition, the model demonstrated the ODB in different arms, with an emphasis on quality of life.

Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer

Background: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRFLI) signals preclinical lymphedema that precedes the development of volumetrically-defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). Methods and Materials: Breast cancer patients planned for axillary dissection and RNI prospectively underwent perometry, NIRFLI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey (LSIDS) and QuickDash) at baseline, after surgery, and at 6, 12, and 18 months following radiation. Clinical lymphedema was defined as an arm volume increase ≥ 5% over baseline. Trends over time were assessed using ANOVA testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. Results: Sixty participants completed at least two sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a BMI >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18mo. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all p<0.05). Both dermal backflow and lymphedema were associated with Quickdash score (p<0.05). Conclusion: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRFLI use to identify patients for early intervention trials following RNI.

Non-Invasive Portable Technologies for Monitoring Breast Cancer Related Lymphedema to Facilitate Telehealth: A Scoping Review.

Breast cancer related lymphedema (BCRL) is a common, debilitating condition that can affect up to one in five breast cancer surviving patients (BCSP). BCRL can significantly reduce the quality of life (QOL) of patients and poses a significant challenge to healthcare providers. Early detection and continuous monitoring of lymphedema is crucial for the development of client-centered treatment plans for post-cancer surgery patients. Therefore, this comprehensive scoping review aimed to investigate the current technology methods used for the remote monitoring of BCRL and their potential to facilitate telehealth in the treatment of lymphedema. Initially, five electronic databases were systematically searched and analyzed following the PRISMA flow diagram. Studies were included, specifically if they provided data on the effectiveness of the intervention and were designed for the remote monitoring of BCRL. A total of 25 included studies reported 18 technological solutions to remotely monitor BCRL with significant methodological variation. Additionally, the technologies were categorized by method of detection and wearability. The findings of this comprehensive scoping review indicate that state-of-the-art commercial technologies were found to be more appropriate for clinical use than home monitoring, with portable 3D imaging tools being popular (SD 53.40) and accurate (correlation 0.9, p 0.05) for evaluating lymphedema in both clinic and home settings with expert practitioners and therapists. However, wearable technologies showed the most future potential for accessible and clinical long-term lymphedema management with positive telehealth outcomes. In conclusion, the absence of a viable telehealth device highlights the need for urgent research to develop a wearable device that can effectively track BCRL and facilitate remote monitoring, ultimately improving the quality of life for patients following post-cancer treatment.

The preventive use of compression sleeve to reduce the risk of clinical lymphedema in patients with breast cancer.

The preventive use of compression sleeve to reduce the risk of clinical lymphedema in patients with breast cancer.

Breast Cancer-Related Lymphedema: The Primary/Secondary Conundrum

Lymphatic Research and BiologyVol. 21, No. 2 EditorialFree AccessBreast Cancer-Related Lymphedema: The Primary/Secondary ConundrumStanley G. RocksonStanley G. RocksonEditor-in-Chief, Stanford University School of Medicine, Stanford, California, USA.Search for more papers by this authorPublished Online:20 Apr 2023https://doi.org/10.1089/lrb.2023.29141.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail For quite some time, within the pages of this journal1–3 and elsewhere,4,5 there has been a persistent theory that there might be systemic and other predispositions to the secondary (or acquired) lymphedema that is encountered frequently as a sequela of breast cancer therapeutics. In addition, it has recently been observed that the presence of a lymphatic disorder such as breast cancer-associated lymphedema can alter the patterns of associated systemic disease expression that exist as comorbidities.6 These phenomena help to blur the distinction between “primary” and “secondary” lymphedema.In the current issue of Lymphatic Research and Biology, we provide three additional sets of original observations that help to expand insights into this hypothesis.In the first of these, Kim and colleagues have explored rates of incidental subclinical lymphedema in the contralateral arm of patients with unilateral postsurgical secondary upper extremity lymphedema. In their study, magnetic resonance imaging of the upper extremities was utilized to examine patients with unilateral upper extremity clinical lymphedema. Axial STIR MR images of the symptomatic and contralateral arms were retrospectively reviewed and edema severity was graded by the investigators. In these 78 examined subjects, contralateral abnormalities were detected in 14.1%. Although the direct conclusion was to emphasize the importance of evaluation of the contralateral limb, the interpretation, by extension, is that there is a disturbance in lymphatic anatomy or function that extends beyond the direct lymphatic trauma of cancer therapeutics.The second investigation, by Furlan and colleagues, examines the phenomenon of blood flow abnormalities in the limb that precede the development of overt lymphedema. In a cohort of 200 subjects, Doppler ultrasound was utilized to examine the axillary and brachial arteries. In these patients, there was detection of higher mean flow velocity and end-diastolic velocity as early as 1 month after surgery. The end-diastolic velocity demonstrated a 73.7% sensitivity and 71.2% specificity as a predictor of long-term lymphedema, with a negative predictive value of 57.6%.The third of these three new investigations proposed a pilot investigation of abdominal fat ratio in subjects with breast cancer-related lymphedema. Here, Nakipoğlu and colleagues investigated the impact of central obesity to the occurrence of this lymphedema presentation. They investigated cohorts of postsurgical subjects with a matched control cohort that differed only in the distribution of BMI. The abdominal circumference measurement demonstrated a modest predictive utility, with a predictive specificity of 89%.In aggregate, these three newly published investigations continue to tantalize us with the increasingly tenable hypothesis that the appearance of acquired lymphedema (in this case following breast cancer therapies) may, and likely does, depend upon systemic factors that predict the likelihood of disease evolution. Continued exploration of these phenomena will, ideally, result in enhanced risk factor stratification, diagnostic evaluation, and, with good fortune, improved risk factor reduction strategies.

Abstract P1-05-16: Bioimpedance Spectroscopy Monitoring Reduces Long-term Clinical Lymphedema Risk

Abstract Background: A prospective surveillance model (PSM) of care can reduce the risk of breast cancer related lymphedema (BCRL). Bioimpedance spectroscopy (BIS) devices can identify sub-clinical BCRL (sBCRL). A recent randomized controlled trial (RCT) demonstrated the benefit of a PSM model of care using BIS over tape measure (TM) but it did not look at the long-term risk following intervention. This work reports the actuarial risk of clinical lymphedema for those who have triggered an intervention for sBCRL by either BIS or TM. Materials and Methods: 879 women with breast cancer were randomized to lymphedema screening with either BIS (n=442) or TM (n=437). Following consent, patients underwent baseline pre-surgical measurements with BIS (L-Dex U400, ImpediMed) and volume (circumference) measurements (Gulick II tape) and randomized after surgery. Both the TM and BIS arms underwent planned post-operative assessments at 3, 6, 12, 18, 24, 30, and 36 months as well at the end of any intervention. Patients with a BIS change from baseline of ≥ 6.5 L-Dex units or TM volume change ≥ 5 and &amp;lt; 10% above pre-surgical baselines "triggered" for sBCRL form the basis of this study. Triggered patients underwent 4-weeks of wearing a class two (23–32 mmHg) compression sleeve and gauntlet for 12 hours per day. TM volume change ≥ 10% was considered clinical BCRL (cBCRL) for all patients who triggered by either BIS or TM. The cumulative incidence of cBCRL was calculated via the Kaplan-Meier method and compared by the Log-rank test. Results: 209 (23.8%) women triggered an intervention and completed treatment for sBCRL (BIS: 89 (20.1%), TM: 120 (27.5%)). The median follow up for the women who triggered was 32.2 months (IQR 17.0 – 33.9) with 30 women (14.4%) women developing cBCRL (BIS: 7 (7.9%), TM: 23 (19.2%)). There was a significant difference in risk between the groups over the follow up interval (log rank test p = 0.021) with the cumulative risk in the BIS group being lower compared to the TM group (Hazard Ratio = 0.38, 95%CI 0.19 – 0.79). The 2- year actuarial risk of cBCRL for triggered patients undergoing lymphedema screening by BIS was 5.0% versus 15.7% for TM screening (p = 0.021, HR = 0.30). The corresponding 3-year rates of cBCRL were 10.3% and 21.2%, (p = 0.031, HR = 0.40) respectively. Conclusions: BIS monitoring for sBCRL with subsequent intervention provides significantly lower risks of cBCRL. The lower triggering rates with BIS highlight its better discrimination of true sBCRL compared to TM and support its use for post-treatment surveillance to detect sBCRL and initiate early intervention. These data suggest that monitoring for sBCRL with BIS and subsequent intervention does not just delay the inevitable progression to cBCRL, but rather prevents it over the duration of the study. Citation Format: John Boyages, Frank Vicini, Chirag Shah. Bioimpedance Spectroscopy Monitoring Reduces Long-term Clinical Lymphedema Risk [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-16.

Abstract P2-14-10: Axillary Reverse Mapping Aids in Reducing the Rates of BCRL in Underserved Ethnically Diverse Population

Abstract Background: Breast Cancer Related Lymphedema (BCRL), is a long-term side effect affecting the patient’s quality of life after lymph node surgery. Historically BCRL is seen in 5-7% and 15-40% of patients undergoing sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) respectively; with the risk increasing two-fold in low-income and ethnic minority groups. Axillary Reverse Mapping (ARM) is a novel technique to distinguish drainage pathways of the arm and breast, and prior studies have reported significantly lower rates of BCRL with ARM. Lymphatic re-approximation can prevent and/or reduce lymphedema rates in cases where crossover nodes are encountered. Furthermore, blue nodes can be preserved during ALND; however, if resected during ALND, lymphatic venous (LYMPHA) procedure can help to restore lymphatic flow. However, there is a paucity of literature looking at the utility of ARM in ethnically minority groups. Therefore, we aimed to evaluate the prevalence of lymphedema in our patient population with breast cancer undergoing SLNB and ALND using ARM and in turn compare these findings to historical controls. Materials &amp; Methods: A retrospective study was carried out on patients who underwent axillary surgery with ARM from January 2019 to July 2021. Patient demographics such as age, BMI, gender, and ethnicity were recorded. Patients undergoing mastectomy vs breast conservation with SLNB ± ALND associated with ARM were monitored for lymphedema for a year at 3-month intervals using SOZO® scores, and then for another 2 years clinically. At each follow-up, SOZO® scores were computed using bioimpedance spectroscopy and compared to preoperative baseline scores. Results: A total of 142 patients’ data was evaluated, of which 83.8% belonged to the minority group (African American = 46, Hispanic = 63, Asian = 10). Mean BMI accounted for 29.1+5.31. Breast conservation surgery and mastectomy were performed in 71.8% (n=102) and 28.1% (n=40) of patients respectively. SLNB was performed on 88.7% (n=126) of the patients and ALND was carried out on 11.3% (n=16). Furthermore, 73.9% (n=105) of the patients underwent radiation therapy. Positive lymph nodes were identified in 24.6% (n=35) of patients. Blue nodes and blue lymphatics were encountered in 17.6% (n=25) and 32.4% (n=46) of patients respectively. Out of the blue nodes identified (n=25), 44% (n=11) were excised and 32% (n=8) were diagnosed as crossover nodes. All the crossover nodes were resected but none of them contributed to the development of lymphedema. Moreover, 90.9% of the patients with blue lymphatics underwent lymphatic re-approximation after excision of the blue nodes. Of the 142 patients, 59 had a three-month follow-up of which 2 patients (3.4%) developed clinical lymphedema diagnosed via SOZO® who had undergone SLNB which resolved by 6-month follow-up. Additionally, compared to the historical incidence of BCRL which accounts for up to 40.4% in ethnic minorities, we found a significantly lower incidence of lymphedema (p&amp;lt; 0.001) in our patient population. Moreover, in our study, ALND and radiation therapy did not contribute to lymphedema rates. Conclusion: ARM procedure can significantly lower BCRL even in ethnically minority groups. 3.4% of patients undergoing SLNB developed BCRL, which was significantly lower than historically reported data. Furthermore, in our study, no patients who underwent ALND developed lymphedema. Also, crossover nodes or radiation therapy did not contribute to the development of lymphedema after surgery demonstrating the effectiveness of ARM technique. Further studies with larger sample size and longer follow-up duration are necessary to better understand the utility of ARM technique in this population. Table 1 Baseline characteristics and follow-up data of the patients undergoing Axillary Reverse Mapping with SLNB ± ALND Citation Format: Fardeen Bhimani, Maureen McEvoy, Kelly Johnson, Sheldon Feldman. Axillary Reverse Mapping Aids in Reducing the Rates of BCRL in Underserved Ethnically Diverse Population [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-10.

Comparison of Lymphatic Drainage of the Lower Limbs After Soft Tissue Reconstruction by Microvascular Muscle Flap Versus Fasciocutaneous Flaps.

Complex traumatic injuries of the lower limb are increasingly being salvaged. The common long-term morbidity includes secondary lymphedema. The role of microvascular flaps is often discussed for lymph flow restoration. However, the differential effect of using muscle flap versus fasciocutaneous flap in the lower-limb trauma to avoid secondary lymphedema is not studied. Forty patients who underwent microvascular flap reconstruction were reviewed retrospectively to obtain data regarding clinical demographics and surgical procedure. Assessment for presence of clinical lymphedema was done. The lymphatic drainage in all these patients was assessed by 99mTc lymphoscintigraphy. Of the 40 patients included in the study, group A (n = 23) underwent muscle-based free flap reconstruction, and group B (n = 17) had fasciocutaneous flaps. Clinical lymphedema was present in 21 patients, of which 18 were of group A and 3 of group B. On lymphoscintigraphy, 14 patients had either partial or complete obstruction in the reconstructed lower limb, 11 in group A and 3 in group B. All of them (n = 14) were found to have associated clinical lymphedema. The association of clinical lymphedema (P < 0.001) and obstructive pattern on lymphoscintigraphy (P < 0.05) with muscle flaps was found to be statistically significant. With the advancement in surgery and techniques, not only salvageability but also stable and morbidity free outcomes are the goals. Fasciocutaneous flaps may have better lymphatic outcomes than the muscle-based flaps, and the criteria for lower-limb reconstruction can be reformed to include simultaneous soft tissue and lymphatic reconstruction.

Topical captopril: a promising treatment for secondary lymphedema

Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-β1 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-β1 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.

T Cell Repertoire Diversity in Lymphedema: Investigating the Antigens Driving the T Cell Response

BACKGROUND: Lymphedema (LE) is a progressive condition that is estimated to affect as many as 1 in 1000 Americans. The disease is a major cause of decreased quality of life and is characterized by swelling, fibrosis, and recurrent infections. Activation of T-helper (Th) inflammatory responses plays a key role in lymphedema development and has been correlated with disease severity. This activation requires interaction with antigen-presenting cells (APCs), suggesting that the T-cell responses occur in response to antigens that are present in tissues after lymphatic injury. Clonal analysis of these T cell responses is significant due to its potential to uncover a common clonal architecture between patients with the disease. Identification of antigen-responsive T cell clones that are selectively expanded has important implications for developing therapies aimed at a common antigen driving the disease process. METHODS: High throughput sequencing (HTS) of clinical lymphedema and normal tissue DNA was utilized to identify unique T cell clones in lymphedematous tissue. Briefly, genomic DNA (gDNA) was isolated from lymphedematous, and control matched upper limb biopsies of six patients. Deep sequencing of the TCR repertoire was conducted by using a two-step biased controlled multiplex PCR to amplify genes of abundant T cell populations. These clones were quantified and characterized by CDR3 sequence length and TCRB Variable (V) gene usage. Predictive analysis of T cell antigen specificity was performed using the Basic Local Alignment Search Tool (BLAST) of the TCR epitope sequences and the activation of antigen-responsive clones was assessed by Flow cytometry. RESULTS: Our analysis demonstrated that the T cell responses in lymphedema are oligoclonal. TCR sequencing of the top five abundant clones in lymphedematous and normal tissue biopsies revealed six conserved amino acid sequences at the CDR3 region unique to the lymphedema group, however, no overlap of T cell repertoires was seen between patients with the disease. BLAST analysis of the corresponding TCRB epitope sequence revealed a list of probable antigens corresponding to each unique clonotype. Of the epitope sequences, unique to LE, staphylococcal enterotoxin represented the highest affinity bacterial antigen, pro-insulin corresponded to the representative self-antigen, and gluten peptide corresponded to plant antigen. CONCLUSION: Our results show that the T cell response in lymphedema is oligoclonal in nature, similar to what is seen in other inflammatory skin diseases such as atopic dermatitis and cutaneous psoriasis. In addition, clonality infers common antigen specificity of a population of T cells. Here we present representative antigens using BLAST analysis of the unique TCRB sequences of clones detected in lymphedematous tissue. Identification of these T cell populations that are selectively expanded in LE may provide a targeted approach for identifying antigenic stimuli or similarly eliminating pathogenic T cell clones as a means of treating the disease.

Lymphatic Function Decreases over Time in the Arms of Breast Cancer Patients following Treatment

Background:In patients with breast cancer-related lymphedema, distinct lymphatic patterns and changed lymphatic contractile function have been described, but it is unknown how these characteristics change over time and to what extent they appear before clinical edema is detectable. Recently, we described the lymphatic morphology and function in a cohort of breast cancer patients shortly after radiation therapy (RT). In the current study, we investigate lymphatic function and morphology in the same cohort after 1 year of follow-up.Methods:The study population consisted of 28 breast cancer patients investigated 12 months after adjuvant locoregional RT. Lymphatic contraction frequency (CF), propulsion velocity, and the morphology of lymphatic vessels in the upper extremities were described in vivo using near-infrared fluorescence imaging. Lymphatic stress test was performed using hyperthermia.Results:At 1 year after RT, (n = 28) 46% of the patients presented with lymphatic morphological abnormalities with a degree of dermal backflow and 21% had developed clinical breast cancer-related lymphedema. In the ipsilateral arm, CF was 23% lower than in the contralateral arm (P = 0.04). Since primary examination, CF in the ipsilateral arm decreased by 40% (P = 0.03), whereas no change was observed in the contralateral arm. During hyperthermia, the ipsilateral arms with lymphatic complications were not able to increase CF as the remaining subgroups.Conclusions:Lymphatic function in the ipsilateral arm deteriorated over time after adjuvant breast cancer therapy. Furthermore, the presence of abnormal torturous lymphatic vessels in asymptomatic arms appeared to be associated with weak lymphatic reserve pumping capacity.

Dual Fluorescent Tracers for Surgical Guidance: Preventing Donor-site Lymphedema in Vascularized Lymph Node Transfer.

Introduction:Vascularized lymph node transfer (VLNT) restores physiological lymphatic function. Although effective, postoperative impairment of donor-site lymphatic function and iatrogenic lymphedema following lymph node transfer remains a pressing concern.Methods:Prospective analysis of VLNT patients undergoing dual fluorescent tracers-assisted harvest was performed at our institution from September 2013 to April 2022. Reverse lymphatic mapping of the lower extremity was performed with indocyanine green (ICG). Blue dye was utilized in both white light and near-infrared spectra for visualization of donor-site lymphatic structures. Demographics, intraoperative details, and surgical outcomes were recorded.Results:Twenty-five patients were included. Median age was 52.9 years with a body mass index of 29.1 kg/m2 and mean follow-up of 44 months (range 24 to 90 months). Lymphedema stage ranged from Campisi 2 to 4. Inguinal VLNT was performed in 13 patients, and 12 patients received combined VLNT and free flap breast reconstruction. No patients required change in lymph node donor site intraoperatively. All ICG stained nodes were preserved in situ. No cases of iatrogenic lower extremity lymphedema were observed. Postoperative bioimpedance spectroscopy, circumferential, and volumetric measurements of the donor-site limb did not show evidence of subclinical or clinical lymphedema. The donor site healed appropriately in 92% of patients; one patient developed methylene blue-induced skin necrosis.Conclusion:Reverse lymphatic mapping and surgical guidance with dual ICG and blue dye fluorescent tracers provides surgeons with real-time surgical guidance without radioisotope, improves surgical visualization in both white light and near-infrared spectra, and avoids iatrogenic lymphatic dysfunction in the donor limb.

Incidence of clinical lymphedema in breast cancer patients treated with adjuvant proton-based radiotherapy.

BackgroundThe purpose of this study was to evaluate the incidence of clinical lymphedema following adjuvant proton-based radiotherapy (RT) in breast cancer (BC) patients.Materials and methodsWe performed a retrospective review of our institutional database to identify BC patients treated with adjuvant proton-based RT. Patients receiving re-irradiation for a BC recurrence or those with a history of ipsilateral chest wall radiation were excluded. Clinical lymphedema was determined by documentation in the chart at baseline and during follow-up.ResultsWe identified 28 patients treated with adjuvant proton-based RT who met the study criteria. Median age at diagnosis was 45 (range, 24–75). Eleven patients (39%) underwent mastectomy, and fourteen (50%) underwent axillary lymph node dissection (ALND). Median number of LNs removed was 6 (range, 1–28). Nineteen patients (68%) received neoadjuvant chemotherapy. Median whole breast/chest wall dose delivered was 50 Gy (range, 44–54.0 Gy). Target volumes included the axillary and supraclavicular lymph nodes in all patients and internal mammary lymph nodes in 27 (96%) patients. Mean dose to the axilla was 49.7 Gy, and mean dose to 95% of the axillary volume (D95) was 46.3 Gy (94% of prescription dose). Mean dose to supraclavicular (SCV) volume was 47.7 Gy, and D95 was 44.1 Gy (91% of prescription dose). Grade 3 dermatitis occurred in 14% of patients. Five patients (18%) had clinical lymphedema, 4 from the ALND subset (n = 14).ConclusionsThe incidence of clinical lymphedema after proton-based RT is comparable to rates reported with photon-based RT with comprehensive nodal coverage.

Epithelial mesenchymal transition of epithelial cells induced by TGF-β signaling in lymphedema

Abstract TGF-β driven fibrosis of the skin is a key pathologic feature of secondary lymphedema. However, the cellular mechanisms that regulate this process remain unknown. Epithelial mesenchymal transition (EMT) is a mechanism by which TGF-β induces fibrosis in other skin diseases. This process is characterized by loss of epithelial cell markers and polarity and increased migratory capacity and invasiveness. Therefore, the purpose of this study was to determine if EMT of skin keratinocytes is activated in lymphedema and if this process is mediated by TGF-β. Using clinical lymphedema biopsy specimens and mouse models of lymphedema, we found that lymphedema results in fibrosis in the papillary dermis and a greater number of rete ridges in the basal layer of epithelium. Keratinocytes in the basal layer of lymphedematous skin express EMT markers (vimentin, fsp1, itgb4, slug, mmp9, twist) and fail to express epithelial markers (keratin14, E-cadherin). Interestingly, we found psamd3 expression in these EMT-like epithelial cells with accumulated TGF-β in papillary dermis by immunohistochemistry. Inhibition of TGF-β signaling markedly decreased EMT and prevented development of fibrosis in a mouse model. To determine if EMT of epithelial cells is induced by lymphedema fluid in skin, we treated keratinocytes with lymph fluid obtained from patients with lymphedema and analyzed in cultures with or without TGF-β inhibitors. We found that keratinocytes cultured with arm fluid only rapidly underwent EMT. In contrast, inhibition of TGF-β signaling prevented this response. Taken together, our findings show for the first time that EMT is activated by TGF-β signaling in lymphedema and that this process plays an important role in the pathology of this disease. Supported by grants from NIH (R01HL111130).

Evaluation of Simplified Lymphatic Microsurgical Preventing Healing Approach (SLYMPHA) for the prevention of breast cancer-related lymphedema after axillary lymph node dissection using bioimpedance spectroscopy

BackgroundLymphedema is a serious complication of axillary lymph node dissection (ALND) with an incidence rate of 20%. Simplified Lymphatic Microsurgical Preventing Healing Approach (SLYMPHA) is a safe and relatively simple method, which decreases incidence of lymphedema dramatically. Our initial study showed an 88% decrease in clinical lymphedema rate. In the initial study, we used arm circumference measurement for the diagnosis of lymphedema and median follow up was 15 months. The aim of this study was to confirm these results after a long-term follow up period and by using bioimpedance spectroscopy (L-Dex) technology in detecting lymphedema. Study designAll patients, undergoing ALND with or without SLYMPHA between January 2014 and November 2020 were included in the study. Patients with no postoperative L-Dex measurements were excluded. A L-Dex score outside the normal range (±10 L-Dex unit) or ≥10 L-Dex unit increase above patient's baseline was considered as lymphedema. The incidence of lymphedema was compared between patients with and without SLYMPHA. Results194 patients were included in the study. 57% of cohort underwent SLYMPHA. Mean follow-up time was 47 ± 37 months. Patients, who underwent SLYMPHA, had a significantly lower rate of lymphedema (16% vs 32%; p = 0.01; OR 0.4 [0.2–0.8]). ConclusionSLYMPHA is a safe and relatively simple method, which continued its efficacy after a long-term follow up period. It should be considered as an adjunct procedure to ALND for all patients during initial surgery.