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.

Early Complications in Prepectoral Tissue Expander-Based Breast Reconstruction.

BACKGROUND: Prepectoral implant placement for postmastectomy breast reconstruction has increased in recent years. Benefits of prepectoral reconstruction may include lack of animation deformities and reduced postoperative pain, but its complication profile is currently unclear. This study aimed to examine the complication profile of prepectoral tissue expanders (TEs) to determine factors associated with TE loss. METHODS: A retrospective review was performed to identify all patients who underwent immediate prepectoral TE reconstruction from January 2018 to June 2021. The decision to use the prepectoral technique was based on mastectomy skin quality and patient comorbidities. Patient demographics, comorbidities, and operative details were evaluated. Outcomes of interest included TE loss, seroma, hematoma, infection/cellulitis, mastectomy skin flap necrosis requiring revision, and TE exposure. Logistic regression analysis was performed to identify factors associated with TE loss. RESULTS: The study identified 1225 TEs. The most frequent complications were seroma (8.7%, n = 106), infection/cellulitis (8.2%, n = 101), and TE loss (4.2%, n = 51). Factors associated with TE loss in the univariate analysis included ethnicity, history of smoking, body mass index, mastectomy weight, and neoadjuvant chemotherapy. In the multivariate regression analysis, only mastectomy weight had a positive association with TE loss (odds ratio, 1.001; p = 0.016). CONCLUSION: Prepectoral two-stage breast reconstruction can be performed safely with an acceptable early complication profile. The study data suggest that increasing mastectomy weight is the most significant factor associated with TE loss. Further research examining the quality of the soft tissue envelope and assessing patient-reported outcomes would prove beneficial.

Commercial Insurance Rates and Coding for Lymphedema Procedures: The Current State of Confusion and Need for Consensus.

BACKGROUND: Surgical treatment of lymphedema has outpaced coding paradigms. In the setting of ambiguity regarding coding for physiologic procedures [lymphovenous bypass (LVB) and vascularized lymph node transplant (VLNT)], we hypothesized that there would be variation in commercial reimbursement based on coding pattern. METHODS: The authors performed a cross-sectional analysis of 2021 nationwide hospital pricing data for 21 CPT codes encompassing excisional (direct excision, liposuction), physiologic (LVB, VLNT), and ancillary (lymphangiography) procedures. Within-hospital ratios (WHRs) and across-hospital ratios (AHRs) for adjusted commercial rates per CPT code quantified price variation. Mixed effects linear regression modeled associations of commercial rate with public payer (Medicare and Medicaid), self-pay, and chargemaster rates. RESULTS: A total of 270,254 commercial rates, including 95,774 rates for physiologic procedures, were extracted from 2863 hospitals. Lymphangiography codes varied most in commercial price (WHR, 1.76 to 3.89; AHR, 8.12 to 44.38). For physiologic codes, WHRs ranged from 1.01 (VLNT; free omental flap) to 3.03 (LVB; unlisted lymphatic procedure), and AHRs ranged from 5.23 (LVB; lymphatic channel incision) to 10.36 (LVB; unlisted lymphatic procedure). Median adjusted commercial rates for excisional procedures ($3635.84) were higher than for physiologic procedures ($2560.40; P < 0.001). Commercial rate positively correlated with Medicare rate for all physiologic codes combined, although regression coefficients varied by code. CONCLUSIONS: Commercial payer-negotiated rates for physiologic procedures were highly variable both within and across hospitals, reflective of variation in CPT codes. Physiologic procedures may be undervalued relative to excisional procedures. Consistent coding nomenclature should be developed for physiologic and ancillary procedures.

Biologic versus synthetic prosthesis for chest wall reconstruction: a matched analysis.

OBJECTIVES: The aim of this study was to compare postoperative outcomes between biologic and synthetic reconstructions after chest wall resection in a matched cohort. METHODS: All patients who underwent reconstruction after full-thickness chest wall resection from 2000 to 2022 were reviewed and stratified by prosthesis type (biologic or synthetic). Biologic prostheses were of biologic origin or were fully absorbable and incorporable. Integer matching was performed to reduce confounding. The study end point was surgical site complications requiring reoperation. Multivariable analysis was performed to identify associated risk factors. RESULTS: In total, 438 patients underwent prosthetic chest wall reconstruction (unmatched: biologic, n = 49; synthetic, n = 389; matched: biologic, n = 46; synthetic, n = 46). After matching, the median (interquartile range) defect size was 83 cm2 (50-142) for the biologic group and 90 cm2 (48-146) for the synthetic group (P = 0.97). Myocutaneous flaps were used in 33% of biologic reconstructions (n = 15) and 33% of synthetic reconstructions (n = 15) in the matched cohort (P = 0.99). The incidence of surgical site complications requiring reoperation was not significantly different between biologic and synthetic reconstructions in the unmatched (3 [6%] vs 29 [7%]; P = 0.99) and matched (2 [4%] vs 4 [9%]; P = 0.68) cohorts. On the multivariable analysis, operative time [adjusted odds ratio (aOR) = 1.01, 95% confidence interval (CI), 1.00-1.01; P = 0.006] and operative blood loss (aOR = 1.00, 95% CI, 1.00-1.00]; P = 0.012) were associated with higher rates of surgical site complications requiring reoperation; microvascular free flaps (aOR = 0.03, 95% CI, 0.00-0.42; P = 0.024) were associated with lower rates. CONCLUSIONS: The incidence of surgical site complications requiring reoperation was not significantly different between biologic and synthetic prostheses in chest wall reconstructions.

The Preferred Design of the Profunda Artery Perforator Flap for Autologous Breast Reconstruction: Transverse or Diagonal?

Background: Since its introduction for autologous breast reconstruction in 2010, the profunda artery perforator (PAP) flap has emerged as a preferred choice when an abdominal flap is suboptimal. The traditional transverse design (tPAP) was popularized, given the inconspicuous donor scar. A diagonal design (dPAP) has since evolved to address some of the shortcomings of the tPAP. The authors aimed to compare outcomes of tPAP/dPAP flaps harvested for breast reconstruction by a single surgeon. Methods: A retrospective review was conducted from 2017 to 2022 of patients undergoing tPAP versus dPAP-based breast reconstruction by a single surgeon at a tertiary cancer center. Patient variables and operative variables were assessed. Need for additional symmetrizing breast procedures were compared. Complications and BREAST-Q patient-reported outcome measures were analyzed. Results: Thirty-nine flaps were used to reconstruct 35 breasts in 24 patients. Average follow-up for the group was 1.8 years. The groups were similar with respect to demographics. The majority of dPAP flaps had two perforators, whereas most tPAP flaps had one perforator. The dPAP flaps had greater average weights, width, and overall surface area. There were no cases of partial/total flap loss. Complications and PROM results were similar between the two groups. Conclusions: The dPAP design allows for a larger skin paddle and greater tissue harvest and capture of cutaneous perforators, without increasing the risk of complications or compromising satisfaction. It should be considered as a viable option in patients unable to undergo abdominal-based reconstruction. Additional patients and multi-institutional efforts are necessary to better compare advantages of either design.

Surgical Management of Textured Breast Implants: Assessing Risk and Analyzing Patient-Reported Outcomes.

BACKGROUND: Textured implants have been linked to breast implant-associated anaplastic large-cell lymphoma. Patients who undergo explantation have options for reconstruction, but data on safety and patient-reported outcomes (PROs) is limited. The purpose of this study was to classify complications and PROs in patients opting for surgical management of textured implants. METHODS: Complication rates and BREAST-Q scores were compared between (i) asymptomatic patients who underwent conversion from textured to smooth implants (n=224), (ii) symptomatic patients who underwent conversion from textured to smooth implants (n=83), (iii) patients who underwent explantation without replacement (n=44), and (iv) patients who underwent replacement with autologous reconstruction (n=33). Linear regression examined PROs controlling for clinical and surgical variables. RESULTS: Overall complication rates in 384 patients (637 implants) differed across groups (p=0.034) with the highest rate (25%) in patients who underwent explantation without replacement. These patients were specifically more impacted by minor complications, notably seroma. Capsulectomy extent did not significantly impact complications. Asymptomatic and symptomatic smooth implant patients had improvements in satisfaction with breasts (<0.05). Autologous reconstruction patients had significant improvements in satisfaction with breasts sustained after 3 months postoperative (p<0.01) and sexual well-being sustained after 6-months postoperative (p<0.05). Patients who underwent removal without replacement had lower physical well-being of the chest scores at ≥1 year than the other groups. CONCLUSIONS: Replacement of textured implants with smooth implants or flaps is safe and is associated with improved satisfaction with breasts and quality of life. The degree of capsulectomy does not appear to impact the incidence of perioperative complications.

A Cohort Analysis of Early Outcomes After AlloDerm, FlexHD, and SurgiMend Use in Two-Stage Prepectoral Breast Reconstruction.

BACKGROUND: Acellular dermal matrix (ADM) is frequently utilized in prepectoral breast reconstruction, but few studies have examined the role of ADM type in complication risk. OBJECTIVES: This study was performed to determine the impact of ADM type on early complication rates in 2-stage alloplastic prepectoral breast reconstruction. METHODS: We performed a cohort examination of all patients who underwent mastectomy with immediate 2-stage alloplastic prepectoral breast reconstruction with ADM support at Memorial Sloan Kettering Cancer Center from 2018 to 2021. ADM types utilized included AlloDerm (LifeCell Corporation, Branchburg, NJ), FlexHD (MTF Biologics, Edison, NJ), and SurgiMend (Integra LifeSciences Corporation, Princeton, NJ). Complication rates based on the number of tissue expanders (TEs) were determined for each ADM type. Performance of multivariate logistic regression determined the impact of ADM type on complication risk after accounting for confounders. RESULTS: Overall, 726 patients (1054 TEs: 194 AlloDerm, 93 FlexHD, 767 SurgiMend) were included. The 3 cohorts differed in terms of mastectomy type (nipple-sparing: 23.5% of AlloDerm, 33.3% of FlexHD, 19.1% of SurgiMend, P = .038); ADM perforation (perforated: 94.8% of AlloDerm, 98.2% of FlexHD, 100% of SurgiMend, P < .001); and ADM size (AlloDerm: 153.2 cm2 [37.6], SurgiMend: 198.7 cm2 [10.4], FlexHD: 223.7 cm2 [37.9], P < .001). On univariate examination, no differences existed between ADM types for seroma, infection, exposure, malposition, or TE loss. Additionally, after adjustment for confounders with multivariate regression, no ADM type had higher odds of TE loss. CONCLUSIONS: In this large cohort of prepectoral reconstruction patients, ADM type did not significantly affect the risk of complications. Additional prospective studies are warranted to better evaluate ADM choice for prepectoral breast reconstruction.

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.

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.

Ensuring patient centeredness in upper extremity lymphedema research: Identifying patient-prioritized agenda and preferences.

PURPOSE: To elicit a patient-prioritized agenda and preferences for upper extremity lymphedema (LE) research. METHODS: Focus group sessions (FGs) were conducted with English-speaking, adult women (18 years and older) with breast cancer-related LE (BCRL) seeking conservative or surgical care at two tertiary cancer centers in Ontario, Canada. An interview guide was used; women were asked to describe health-related quality of life (HRQL) outcomes that mattered the most to them, followed by their preferences for research study design and for providing patient-reported outcomes measure (PROM) data. Inductive content analysis was used to identify themes and subthemes. RESULTS: A total of 16 women participated in 4 FG sessions (55 ± 9.5 years) and described the impact of LE on their appearance, physical, psychosocial, and sexual well-being. Women emphasized that psychosocial well-being was often not discussed in clinical care and that they were poorly informed of LE risk and care options. Most women said that they would not be willing to be randomized to surgical versus conservative management of LE. They also expressed a preference to complete PROM data electronically. All women emphasized the value of having an open text option alongside PROMs to expand on their concerns. CONCLUSION: Patient centeredness is key to generating meaningful data and ensuring ongoing engagement in clinical research. In LE, comprehensive PROMs that measure a range of HRQL concerns, especially psychosocial well-being, should be considered. Women with BCRL are reluctant to be randomized to conservative care when a surgical option is available, resulting in implications for planning trial sample size and recruitment.

Early Complications in Prepectoral Breast Reconstructions with and without Acellular Dermal Matrix: A Preliminary Analysis of Outcomes.

BACKGROUND: Prepectoral tissue expander (TE) placement for two-stage postmastectomy reconstruction is usually performed in conjunction with insertion of acellular dermal matrix (ADM). However, the effects of ADM use on TE loss or other early complications remain unknown. Therefore, the aim of this study was to compare early postoperative complications in patients who underwent prepectoral breast implant reconstruction with or without ADM use. METHODS: We performed a retrospective cohort study of all patients at our institution who underwent prepectoral breast reconstruction from January 2018 to June 2021. The primary outcome was TE loss within 90 days of surgery; secondary outcomes included other complications including infection, TE exposure, mastectomy skin flap necrosis requiring revision, and seroma. RESULTS: Data on 714 patients with 1,225 TEs (1,060 with ADM, 165 without) were analyzed. Baseline demographics did not differ by ADM use, though mastectomy breast tissue weight was higher in patients without ADM (750.3 g vs. 540.8 g, p < 0.001). Rates of TE loss were similar in reconstructions with (3.8 percent) ADM and without (6.7 percent; p = 0.09). We also did not find differences in the rates of secondary outcomes between cohorts. CONCLUSIONS: ADM use had no statistically significant effect on early complication rates among patients undergoing breast reconstruction with prepectoral TEs. Still, we were underpowered and data trended toward statistical significance, so larger studies are required in the future. Additional research and randomized studies should focus on larger cohorts and examine long-term complications such as capsular contracture and implant malposition.

The contribution of microvascular free flaps and pedicled flaps to successful chest wall surgery.

OBJECTIVE: Pedicled flaps (PFs) have historically served as the preferred option for reconstruction of large chest wall defects. More recently, the indications for microvascular-free flaps (MVFFs) have increased, particularly for defects in which PFs are inadequate or unavailable. We sought to compare oncologic and surgical outcomes between MVFFs and PFs in reconstructions of full-thickness chest wall defects. METHODS: We retrospectively identified all patients who underwent chest wall resection at our institution from 2000 to 2022. Patients were stratified by flap reconstruction. End points were defect size, rate of complete resection, rate of local recurrence, and postoperative outcomes. Multivariable analysis was performed to identify factors associated with complications at 30 days. RESULTS: In total, 536 patients underwent chest wall resection, of whom 133 had flap reconstruction (MVFF, n = 28; PF, n = 105). The median (interquartile range) covered defect size was 172 cm2 (100-216 cm2) for patients receiving MVFF versus 109 cm2 (75-148 cm2) for patients receiving PF (P = .004). The rate of R0 resection was high in both groups (MVFF, 93% [n = 26]; PF, 86% [n = 90]; P = .5). The rate of local recurrence was 4% in MVFF patients (n = 1) versus 12% in PF patients (n = 13, P = .3). Postoperative complications were not statistically different between groups (odds ratio for PF, 1.37; 95% confidence interval, 0.39-5.14]; P = .6). Operative time >400 minutes was associated with 30-day complications (odds ratio, 3.22; 95% confidence interval, 1.10-9.93; P = .033). CONCLUSIONS: Patients with MVFFs had larger defects, a high rate of complete resection, and a low rate of local recurrence. MVFFs are a valid option for chest wall reconstructions.

Air versus Saline in Initial Prepectoral Tissue Expansion: A Comparison of Complications and Perioperative Patient-Reported Outcomes.

BACKGROUND: One option to optimize prepectoral tissue expander fill volume while minimizing stress on mastectomy skin flaps is to use air as an initial fill medium, with subsequent exchange to saline during postoperative expansion. The authors compared complications and early patient-reported outcomes (PROs) based on fill type in prepectoral breast reconstruction patients. METHODS: Prepectoral breast reconstruction patients who underwent intraoperative tissue expansion with air or saline from 2018 to 2020 were reviewed to assess fill-type utilization. The primary endpoint was expander loss; secondary endpoints included seroma, hematoma, infection/cellulitis, full-thickness mastectomy skin flap necrosis requiring revision, expander exposure, and capsular contracture. PROs were assessed with the BREAST-Q Physical Well-Being of the Chest scale 2 weeks postoperatively. Propensity-matching was performed as a secondary analysis. RESULTS: Of 560 patients (928 expanders) included in the analysis, 372 had devices initially filled with air (623 expanders), and 188 with saline (305 expanders). No differences were observed for overall rates of expander loss (4.7% versus 3.0%, P = 0.290) or overall complications (22.5% versus 17.7%, P = 0.103). No difference in BREAST-Q scores was observed ( P = 0.142). Utilization of air-filled expanders decreased substantially over the last study year. After propensity matching, no differences in loss, other complications, or PROs were observed across cohorts. CONCLUSIONS: Tissue expanders initially filled with air seem to have no significant advantage over saline-filled expanders in maintaining mastectomy skin flap viability or PROs, including after propensity matching. These findings can help guide choice of initial tissue expander fill type. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

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.

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.

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema.

Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.

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.