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.

The Impact of Lymphedema on Patient-Reported Outcomes After Breast Reconstruction: A Preliminary Propensity Score-Matched Analysis.

BACKGROUND: Studies on the impact of secondary lymphedema on patient-reported satisfaction and quality of life following postmastectomy breast reconstruction are limited by their heterogeneity. We aimed to reduce heterogeneity in study sample populations and compare BREAST-Q Reconstruction Module scores of patients with lymphedema matched to patients without lymphedema. METHODS: We identified patients who underwent postmastectomy breast reconstruction from 2009 to 2017 and performed a propensity score-matched analysis to compare patient-reported outcomes of patients who developed lymphedema with those who did not. Matched covariates included age, body mass index, race/ethnicity, smoking history, radiation or chemotherapy exposure, postoperative infection, and reconstruction modality and laterality. Outcomes of interest were pre- and postoperative BREAST-Q scores for Satisfaction with Breasts, Physical Well-being of the Chest, Sexual Well-Being, and Psychosocial Well-Being; the minimal clinically important difference (MCID) was four points. RESULTS: Matched cohorts included 322 patients per group. Preoperative BREAST-Q scores did not differ between lymphedema and non-lymphedema matched cohorts. Postoperative BREAST-Q scores were significantly lower in lymphedema patients: Physical Well-Being of the Chest (all time points), Satisfaction with Breast (at 1 and 2 years), Sexual Well-Being (at 2 years), and Psychosocial Well-Being (at 2 and 3 years). All significant differences in average scores were greater than the MCID. CONCLUSIONS: Patients with breast cancer-related lymphedema reported significantly lower Physical Well-Being of the Chest, Satisfaction with Breasts, Sexual Well-Being, and Psychosocial Well-Being at various time points. Our findings may prove useful for patient counseling and justify the need for further research on the prevention and treatment of this devastating disease.

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.

Accuracy, Sensitivity, and Specificity of the LLIS and ULL27 in Detecting Breast Cancer-Related Lymphedema.

INTRODUCTION: Breast cancer-related lymphedema occurs in up to 30% of women following axillary lymph node dissection (ALND) and less commonly following sentinel lymph node biopsy. To quantify disability in these patients, patient-reported outcome measures (PROMs) have proven useful; however, given the overlap of symptoms between ALND and lymphedema, examination of their accuracy, sensitivity, and specificity in detecting lymphedema in breast cancer patients undergoing ALND is needed. METHODS: The Lymphedema Life Impact Scale (LLIS) and the Upper Limb Lymphedema 27 scale (ULL27) were administered to patients who had undergone ALND at least 2 years prior and either did or did not develop lymphedema. Survey responses and the degree of disability were compared to generate receiver operator characteristic (ROC) curves, and the sensitivity and specificity of PROMs to diagnose lymphedema were analyzed. RESULTS: Both PROMs were highly accurate, sensitive, and specific for detecting lymphedema. The LLIS had an accuracy of 97%, sensitivity of 100%, and specificity of 84.8% at a cutoff of ≥ 5.88 overall percent impairment score (higher scores indicate worse disability). The ULL27 had an accuracy of 93%, sensitivity of 88.6%, and specificity of 90.9% at a cutoff of ≤ 83.3 global score (lower scores indicate worse disability). CONCLUSIONS: The LLIS and the ULL27 appear to be highly specific for lymphedema and capable of differentiating it from symptoms resulting from ALND alone. Our findings suggest that use of these questionnaires with a threshold may be effective for diagnosing lymphedema, potentially reducing the need for frequent clinic visits and time-consuming measurements.

Prevention, Surveillance, and Treatment of Breast Cancer-Related Lymphedema: The Role of the Advanced Practice Provider.

Breast cancer-related lymphedema is a lifelong disease associated with decreased quality of life and increased healthcare costs. Evidence supports early detection and prompt treatment through prospective surveillance models.

Accessory Lymphatic Drainage Pathways on Indocyanine Green Lymphography in Patients with Breast Cancer-Related Lymphedema.

BACKGROUND: Current predictive models of lymphedema risk cannot predict with 100% certainty which patients will go on to develop lymphedema and which will not. Patient-specific anatomic and physiologic differences may be the missing factor. The authors hypothesize that patients with accessory lymphatic pathways may have improved lymphatic drainage, resulting in smaller limb volumes. METHODS: The authors reviewed indocyanine green (ICG) lymphography images of all patients who presented to their institution for evaluation of breast cancer-related lymphedema. Patients with unilateral upper extremity lymphedema, a full set of bilateral limb measurements, and ICG images of both limbs were included. Other variables of interest included patient demographics and length of follow-up. Patients with accessory pathways were determined independently, and conflicts were resolved with discussion. Abnormal images were also evaluated for common drainage pathways. RESULTS: Thirty patients were identified as having accessory lymphatic drainage pathways. These patients had significantly smaller limb volume differences [8.19% (SD, 11.22)] compared with patients who did not exhibit these pathways [20.74% (SD, 19.76); P < 0.001]. The most common pathway was absence or rerouting of the radial bundle to the ulnar or volar bundles ( n = 16). CONCLUSIONS: The ability to create accessory lymphatic drainage pathways may be associated with improved lymphatic drainage, resulting in smaller limb volumes. Furthermore, certain drainage pathways appear to be more common than others. Description of these pathways should be considered for inclusion in ICG lymphography image grading criteria. Further study is needed to clarify the nature of these pathways and whether these pathways affect subjective symptoms and quality of life. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Feasibility and Clinical Utility of Prediction Models for Breast Cancer-Related Lymphedema Incorporating Racial Differences in Disease Incidence.

Importance: Breast cancer-related lymphedema (BCRL) is a common complication of axillary lymph node dissection (ALND) but can also develop after sentinel lymph node biopsy (SLNB). Several models have been developed to predict the risk of disease development before and after surgery; however, these models have shortcomings that include the omission of race, inclusion of variables that are not readily available to patients, low sensitivity or specificity, and lack of risk assessment for patients treated with SLNB. Objective: To create simple and accurate prediction models for BCRL that can be used to estimate preoperative or postoperative risk. Design, Setting, and Participants: In this prognostic study, women with breast cancer who underwent ALND or SLNB from 1999 to 2020 at Memorial Sloan Kettering Cancer Center and the Mayo Clinic were included. Data were analyzed from September to December 2022. Main Outcomes and Measures: Diagnosis of lymphedema based on measurements. Two predictive models were formulated via logistic regression: a preoperative model (model 1) and a postoperative model (model 2). Model 1 was externally validated using a cohort of 34 438 patients with an International Classification of Diseases diagnosis of breast cancer. Results: Of 1882 included patients, all were female, and the mean (SD) age was 55.6 (12.2) years; 80 patients (4.3%) were Asian, 190 (10.1%) were Black, 1558 (82.8%) were White, and 54 (2.9%) were another race (including American Indian and Alaska Native, other race, patient refused to disclose, or unknown). A total of 218 patients (11.6%) were diagnosed with BCRL at a mean (SD) follow-up of 3.9 (1.8) years. The BCRL rate was significantly higher among Black women (42 of 190 [22.1%]) compared with all other races (Asian, 10 of 80 [12.5%]; White, 158 of 1558 [10.1%]; other race, 8 of 54 [14.8%]; P < .001). Model 1 included age, weight, height, race, ALND/SLNB status, any radiation therapy, and any chemotherapy. Model 2 included age, weight, race, ALND/SLNB status, any chemotherapy, and patient-reported arm swelling. Accuracy was 73.0% for model 1 (sensitivity, 76.6%; specificity, 72.5%; area under the receiver operating characteristic curve [AUC], 0.78; 95% CI, 0.75-0.81) at a cutoff of 0.18, and accuracy was 81.1% for model 2 (sensitivity, 78.0%; specificity, 81.5%; AUC, 0.86; 95% CI, 0.83-0.88) at a cutoff of 0.10. Both models demonstrated high AUCs on external (model 1: 0.75; 95% CI, 0.74-0.76) or internal (model 2: 0.82; 95% CI, 0.79-0.85) validation. Conclusions and Relevance: In this study, preoperative and postoperative prediction models for BCRL were highly accurate and clinically relevant tools comprised of accessible inputs and underscored the effects of racial differences on BCRL risk. The preoperative model identified high-risk patients who require close monitoring or preventative measures. The postoperative model can be used for screening of high-risk patients, thus decreasing the need for frequent clinic visits and arm volume measurements.

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.

Understanding the Relationship between Activity and Neighbourhoods (URBAN) Study: research design and methodology.

BACKGROUND: Built environment attributes are recognized as being important contributors to physical activity (PA) engagement and body size in adults and children. However, much of the existing research in this emergent public health field is hindered by methodological limitations, including: population and site homogeneity, reliance on self-report measures, aggregated measures of PA, and inadequate statistical modeling. As an integral component of multi-country collaborative research, the Understanding the Relationship between Activity and Neighbourhoods (URBAN) Study seeks to overcome these limitations by determining the strengths of association between detailed measures of the neighborhood built environment with PA levels across multiple domains and body size measures in adults and children. This article outlines the research protocol developed for the URBAN Study. METHODS AND DESIGN: The URBAN Study is a multi-centered, stratified, cross-sectional research design, collecting data across four New Zealand cities. Within each city, 12 neighborhoods were identified and selected for investigation based on higher or lower walkability and Maori demographic attributes. Neighborhoods were selected to ensure equal representation of these characteristics. Within each selected neighborhood, 42 households are being randomly selected and an adult and child (where possible) recruited into the study. Data collection includes: objective and self-reported PA engagement, neighborhood perceptions, demographics, and body size measures. The study was designed to recruit approximately 2,000 adults and 250 children into the project. Other aspects of the study include photovoice, which is a qualitative assessment of built environment features associated with PA engagement, an audit of the neighborhood streetscape environment, and an individualized neighborhood walkability profile centered on each participant's residential address. Multilevel modeling will be used to examine the individual-level and neighborhood-level relationships with PA engagement and body size. DISCUSSION: The URBAN Study is applying a novel scientifically robust research design to provide urgently needed epidemiological information regarding the associations between the built environment and health outcomes. The findings will contribute to a larger, international initiative in which similar neighborhood selection and PA measurement procedures are utilized across eight countries. Accordingly, this study directly addresses the international priority issues of increasing PA engagement and decreasing obesity levels.

Associations Between the Neighborhood Environment and Moderate-to-Vigorous Walking in New Zealand Children: Findings from the URBAN Study.

BACKGROUND: Urban design may affect children's habitual physical activity by influencing active commuting and neighborhood play. PURPOSE: Our objective was to examine associations between neighborhood built-environment features near children's homes and objectively measured physical activity. METHODS: We used geographical information system (GIS) protocols to select 2016 households from 48 low- and high-walkability neighborhoods within four New Zealand cities. Children (n = 227; mean age ± standard deviation [SD] 9.3 ± 2.1 years) from the selected households wore accelerometers that recorded physical activity in the period 2008-2010. We used multilevel linear models to examine the associations of GIS and street-audit measures, using the systematic pedestrian and cycling environmental scan (SPACES), of the residential environment (ranked into tertiles) on children's hourly step counts and proportions of time spent at moderate-to-vigorous intensity on school and non-school days. RESULTS: During school-travel times (8:00-8:59 a.m. and 15:00-15:59 p.m.), children in the mid-tertile distance from school (~1 to 2 km) were more active than children with shorter or longer commute distances (1290 vs. 1130 and 1140 steps·h(-1); true between-child SD 440). After school (16:00-17:59 p.m.), children residing closest to school were more active (890 vs. 800 and 790 steps·h(-1); SD 310). Neighborhoods with more green space, attractive streets, or low-walkability streets showed a moderate positive association on non-school day moderate-to-vigorous steps, whereas neighborhoods with additional pedestrian infrastructure or more food outlets showed moderate negative associations. Other associations of residential neighborhoods were unclear but, at most, small. CONCLUSIONS: Designing the urban environment to promote safe child-pedestrian roaming may increase children's moderate-to-vigorous physical activity.

Associations of objectively measured built-environment attributes with youth moderate-vigorous physical activity: a systematic review and meta-analysis.

BACKGROUND: Understanding attributes of the built environment that influence children's and adolescents' habitual physical activity can inform urban design. OBJECTIVE: To conduct a systematic review and meta-analysis of studies linking aspects of the built environment with youth moderate-vigorous activity, including walking. DATA SOURCES: The PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched using relevant key words for articles published between January 2000 and March 2013. STUDY SELECTION: The included articles reported associations between children's or adolescents' objectively measured physical activity and residential neighbourhoods or activity settings defined with geographical information systems (GIS), street audits or global positioning systems (GPS). Excluded articles did not delineate neighbourhoods by residential address or were not written in English. Of 320 potentially relevant articles, 31 met the inclusion criteria, but only 23 (with a total of 6,175 participants, aged 8-17 years) provided sufficient data to derive effects (associations) of built-environment features on child or adolescent habitual moderate-vigorous activity. STUDY APPRAISAL AND SYNTHESIS METHODS: Ten criteria were used to appraise the inclusion of studies. The effects were analysed as the difference in mean minutes of daily moderate-vigorous activity either between two levels of a dichotomous variable (e.g., neighbourhood park available or not within 800 m) or between predicted means corresponding to a difference of two standard deviations of a simple linear numeric variable (e.g., housing density per square kilometre). The magnitude of the difference in means was evaluated via standardization. The meta-analysis was performed with the 14 studies using GIS or street audits to relate a total of 58 specific built-environment features to daily activity. Each feature was categorized with two dichotomous variables to indicate whether the feature promoted playing and/or walking, and these variables were included in the meta-analytic model as moderators interacting with age and proportion of males in the study as linear numeric covariates. RESULTS: The meta-analysed effects of built-environment features that encourage play (including sports and fitness) and/or walking on youth moderate-vigorous activity ranged between trivial and small. There was a moderate effect of age (15 versus 9 years) whereby play facilities, parks, playgrounds and features that facilitate walking had negative effects on children's activity but positive effects on adolescents' activity. In studies that located youth physical activity with GPS, walking to school produced small increases in activity compared with transport by car or bus, greater proportions of activity took place in streets and urban venues (40-80%) than in green spaces (20-50%), and more than half of children's outdoor activity occurred with a parent nearby. LIMITATIONS: The meta-analysis cannot quantify the additive effect when several built-environment features are provided in a given neighbourhood. CONCLUSIONS: Children do not benefit to the same extent as adolescents from built-environment features that encourage walking and those designed or used for neighbourhood play.