Lymphovenous Bypass for Immediate Lymphatic Reconstruction in Breast Cancer Patients Undergoing Axillary Lymph Node Dissection: Minimizing the Risk of Upper Extremity Lymphedema.

BACKGROUND: Studies have shown a significant reduction in breast cancer-related lymphedema (BCRL) rates in patients undergoing complete axillary lymph node dissection (cALND) combined with immediate lymphatic reconstruction (ILR) using lymphovenous bypass (LVB).The purpose of this study was to determine if ILR with LVB at the time of cALND results in a decreased incidence of BCRL and its impact on patient quality of life (QOL). METHODS: In this prospective cohort study, patients ≥ 18 years requiring cALND underwent ILR from 2019 to 2021. The primary outcome was bilateral upper limb volumes measured by Brørson's truncated cone formula and the Pero-System (3D Körper Scanner). The secondary outcome was QOL measured by the Lymphedema Quality of Life (LYMQOL) arm patient-reported outcome measurement. RESULTS: Forty-two patients consented to ILR using LVB. ILR was completed in 41 patients with a mean of 1.9 ± 0.9 lymphovenous anastomosis performed. Mean age of patients was 52.4 ± 10.5 years with a mean body mass index of 27.5 ± 4.9 kg/m2. All patients (n = 39, 100%) received adjuvant therapy after ILR. Mean follow-up was 15.2 ± 5.1 months. Five patients met criteria for lymphedema throughout the duration of the study (12.8%), with two patients having resolution, with an overall incidence of 7.7% by the end of the study period. Patients with lymphedema were found to have statistically significant lower total LYMQOL values at 18 months (8.44 ± 1.17 vs. 3.23 ± 0.56, p < 0.001). A mean increase of 0.73 ± 3.5 points was observed for overall QOL average for upper limb function at 18 months compared with 3 months (t = 0.823, p = 0.425). CONCLUSION: This study showed an incidence of 7.7% lymphedema development throughout the duration of study. We also showed that ILR has the potential to reduce the significant long-term adverse outcomes of lymphedema and improve QOL for patients undergoing cALND.

Implementation, results and face validity of the Consultation and Relational Empathy measure in a Canadian department of surgery.

BACKGROUND: The Consultation and Relational Empathy (CARE) Measure, a validated questionnaire designed to assess patients' perceptions of their physician's communication skills and empathy, has been used to assess empathy in medical specialties but has seldom been applied to surgery. We assessed empathy and communication skills among a group of surgeons within a single academic institution. METHODS: All surgeons within our department of surgery were invited to participate. Patients seen in clinics of participating surgeons were recruited prospectively from July 2018 to February 2019. At the end of each clinical encounter, they were asked to complete a CARE survey. Surveys were analyzed according to previously validated inclusion and exclusion criteria. We calculated mean scores for each surgeon and surgical division. About 6 months after study completion, surgeons were provided with their individual score and de-identified division scores, and were asked to complete a follow-up survey assessing their attitudes toward the CARE Measure. RESULTS: Of the 82 surgeons invited, 51 (62%) agreed to participate; 7 had fewer than 25 completed surveys and were excluded from analysis. A total of 1801 surveys for 44 surgeons (33 male and 11 female) were included in the final analysis. The average CARE score across the department was 46.9 (95% confidence interval [CI] 46.6-47.1). Female surgeons received significantly higher scores than male surgeons (mean 47.6 [95% CI 47.1-48.0] v. 46.7 [95% CI 46.4-48.0]). Of the 35 surgeons who responded to the follow-up survey, 31 (89%) felt that the questions in the CARE Measure applied to their practice, and half of these reported that they intended to make changes in response to the feedback. CONCLUSION: We found high communication and empathy scores among surgeons in the outpatient setting, with enough variability to encourage continued improvement. The CARE Measure appears to have face validity among surgeons, and the vast majority found it relevant to their practice. Further study is needed to formally assess the relevance, performance, reliability and construct validity of this measure.

A nude mouse model of hypertrophic scar shows morphologic and histologic characteristics of human hypertrophic scar.

Hypertrophic scar (HSc) is a fibroproliferative disorder that occurs following deep dermal injury. Lack of a relevant animal model is one barrier toward better understanding its pathophysiology. Our objective is to demonstrate that grafting split-thickness human skin onto nude mice results in survival of engrafted human skin and murine scars that are morphologically, histologically, and immunohistochemically consistent with human HSc. Twenty nude mice were xenografted with split-thickness human skin. Animals were euthanized at 30, 60, 120, and 180 days postoperatively. Eighteen controls were autografted with full-thickness nude mouse skin and euthanized at 30 and 60 days postoperatively. Scar biopsies were harvested at each time point. Blinded scar assessment was performed using a modified Manchester Scar Scale. Histologic analysis included hematoxylin and eosin, Masson's trichrome, toluidine blue, and picrosirius red staining. Immunohistochemistry included anti-human human leukocyte antigen-ABC, α-smooth muscle actin, decorin, and biglycan staining. Xenografted mice developed red, shiny, elevated scars similar to human HSc and supported by blinded scar assessment. Autograft controls appeared morphologically and histologically similar to normal skin. Xenografts survived up to 180 days and showed increased thickness, loss of hair follicles, adnexal structures and rete pegs, hypercellularity, whorled collagen fibers parallel to the surface, myofibroblasts, decreased decorin and increased biglycan expression, and increased mast cell density. Grafting split-thickness human skin onto nude mice results in persistent scars that show morphologic, histologic, and immunohistochemical consistency with human HSc. Therefore, this model provides a promising technique to study HSc formation and to test novel treatment options.

Human hypertrophic scar-like nude mouse model: characterization of the molecular and cellular biology of the scar process.

Hypertrophic scar (HTS) following thermal injury and other forms of trauma is a dermal fibroproliferative disorder that leads to considerable morbidity. Because of the lack of an ideal animal model, research is difficult. We have established an HTS model that involves transplanting human split-thickness skin graft (STSG) or full-thickness skin graft (FTSG) onto the backs of nude mice. The animals developed raised, firm, and reddish scars 2 months following transplantation. Histology and micromeasurement indicate raised, thickened engrafted skin with STSG and FTSG. In contrast, thickening was not observed with full-thickness rat skin grafts used as controls. Masson's trichrome staining demonstrates increased accumulations of collagen fibrils in the dermis in both scars grafted with STSG and FTSG. Staining cells with toludine blue and an antibody for F4/80 showed an increase in the infiltration of mast cells and macrophages. Quantification of fibrocytes reveals increased fibrocytes. Moreover, STSG grafted skin had significantly more macrophages, mast cells, and fibrocytes than FTSG. Real-time polymerase chain reaction analysis showed significantly elevated mRNA levels for type I collagen, transforming growth factor-ß, connective tissue growth factor and heat shock protein 47 in both types of engrafted skin. These data demonstrate that human skin grafted onto nude mice develops red raised and thickened scars having intrinsic properties that closely resemble HTS formation as seen in humans. Interestingly, STSG developed more scar than FTSG. Furthermore, inflammatory cells and bone marrow-derived fibrocytes may play a critical role in HTS development in this animal model.

A Randomized Controlled Trial Comparing Alloderm-RTU with DermACELL in Immediate Subpectoral Implant-Based Breast Reconstruction.

BACKGROUND: The effectiveness of different acellular dermal matrices (ADM) used for implant-based reconstruction immediately following mastectomy is an important clinical question. A prospective randomized clinical trial was performed to evaluate the superiority of DermACELL over Alloderm-RTU in reducing drain duration. METHODS: Patients undergoing mastectomy with subpectoral immediate and permanent implant-based breast reconstruction were randomized to Alloderm-RTU or DermACELL. The primary outcome was seroma formation, measured by the duration of postoperative drain placement. Secondary outcomes included: post drain removal seroma aspiration, infection, redbreast syndrome, wound dehiscence, loss of the implant, and unplanned return to the operating room. RESULTS: 62 patients were randomized for 81 mastectomies (41 Alloderm-RTU, 40 DermACELL). Baseline characteristics were similar. There was no statistically significant difference in mean drain duration (p = 0.16), with a trend towards longer duration in the Alloderm-RTU group (1.6 days; 95%CI, 0.7 to 3.9). The overall rate of minor and major complications were statistically similar between the two groups; although patients with Alloderm-RTU had 3 times as many infections requiring antibiotics (7.9% vs. 2.5%) with a risk difference of 5.4 (95%CI -4.5 to 15.2), and twice as many unplanned returns to the operating room (15.8% vs. 7.5%) with a risk difference of 8.3 (95% CI -5.9 to 22.5) as DermACELL. CONCLUSION: This is the first prospective randomized clinical trial comparing the two most commonly used human-derived ADMs. There was no statistically significant difference in drain duration, minor, or major complications between DermACELL over Alloderm-RTU in immediate subpectoral permanent implant-based breast reconstruction post-mastectomy.

Economics of Lymphovenous Bypass.

BACKGROUND: The objective of this study was to compare the economic impact of complete decongestive therapy and lymphovenous bypass in the management of upper extremity lymphedema. METHODS: Economics were modeled for a patient with breast cancer-related lymphedema undergoing three different clinical pathways: (1) complete decongestive therapy alone; (2) lymphovenous bypass no longer requiring ongoing complete decongestive therapy; or (3) lymphovenous bypass requiring ongoing complete decongestive therapy. Activity-based cost analysis identified costs incurred with complete decongestive therapy and lymphovenous bypass. Costs were retrieved from supplier price lists, physician fee schedules, lymphedema therapists, and literature reviews. The net present value of all costs incurred for each clinical pathway were calculated. RESULTS: The estimated net present value of all costs for a patient with breast cancer-related lymphedema undergoing treatment were as follows: (1) complete decongestive therapy alone ($30,400); (2) lymphovenous bypass no longer requiring ongoing complete decongestive therapy ($15,000); or (3) lymphovenous bypass requiring ongoing complete decongestive therapy ($42,100). The expected net present value of all costs for lymphovenous bypass was $26,800, which was comparable to that of complete decongestive therapy alone. Sensitivity analysis demonstrated that the expected net present value of lymphovenous bypass was dependent on the patient's life expectancy, number of bypass anastomoses, and likelihood of discontinuing complete decongestive therapy. CONCLUSIONS: Lymphedema has substantial ongoing costs irrespective of the treatment modality. The cost of lymphovenous bypass appears comparable to that of complete decongestive therapy alone-the surgical costs of lymphovenous bypass are offset by the savings from discontinued ongoing therapy. Despite its limitations as a theoretical economic model, this study provides insight into the potential economic impact of lymphovenous bypass.

Morphologic and Histologic Comparison of Hypertrophic Scar in Nude Mice, T-Cell Receptor, and Recombination Activating Gene Knockout Mice.

BACKGROUND: Proliferative scars in nude mice have demonstrated morphologic and histologic similarities to human hypertrophic scar. Gene knockout technology provides the opportunity to study the effect of deleting immune cells in various disease processes. The authors' objective was to test whether grafting human skin onto T-cell receptor (TCR) αß-/-γδ-/-, recombination activating gene (RAG)-1-/-, and RAG-2γ-/-c-/- mice results in proliferative scars consistent with human hypertrophic scar and to characterize the morphologic, histologic, and cellular changes that occur after removing immune cells. METHODS: Nude TCRαß-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice (n = 20 per strain) were grafted with human skin and euthanized at 30, 60, 120, and 180 days. Controls (n = 5 per strain) were autografted with mouse skin. Scars and normal skin were harvested at each time point. Sections were stained with hematoxylin and eosin, Masson's trichrome, and immunohistochemistry for anti-human leukocyte antigen-ABC, α-smooth muscle actin, decorin, and biglycan. RESULTS: TCRαß-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice grafted with human skin developed firm, elevated scars with histologic and immunohistochemical similarities to human hypertrophic scar. Autografted controls showed no evidence of pathologic scarring. Knockout animals demonstrated a capacity for scar remodeling not observed in nude mice where reductions in α-smooth muscle actin staining pattern and scar thickness occurred over time. CONCLUSIONS: Human skin transplanted onto TCRαß-/-γδ-/-, RAG-1-/-, and RAG-2-/-γc-/- mice results in proliferative scars with morphologic and histologic features of human hypertrophic scar. Remodeling of proliferative scars generated in knockout animals is analogous to changes in human hypertrophic scar. These animal models may better represent the natural history of human hypertrophic scar.

Novel methods for the investigation of human hypertrophic scarring and other dermal fibrosis.

Hypertrophic scar (HTS) represents the dermal equivalent of fibroproliferative disorders that occur after injury involving the deep dermis while superficial wounds to the skin heal with minimal or no scarring. HTS is characterized by progressive deposition of collagen that occurs with high frequency in adult dermal wounds following traumatic or thermal injury. Increased levels of transforming growth factor-ß1 (TGF-ß1), decreased expression of small leucine-rich proteoglycans (SLRPs), and/or fibroblast subtypes may influence the development of HTS. The development of HTS is strongly influenced by the cellular and molecular properties of fibroblast subtypes, where cytokines such as fibrotic TGF-ß1 and CTGF as well as the expression of SLRPs, particularly decorin and fibromodulin, regulate collagen fibrillogenesis and the activity of TGF-ß1. Reduced anti-fibrotic molecules in the ECM of the deep dermis and the distinctive behavior of the fibroblasts in this region of the dermis which display increased sensitivity to TGF-ß1's biological activity contribute to the development of HTS following injury to the deep dermis. By comparing the cellular and molecular differences involved in deep and superficial wound healing in an experimental wound scratch model in humans that has both superficial and deep injuries within the same excisional model, our aim is to increase our understanding of how tissue repair following injury to the deep dermis can be changed to promote healing with a similar pattern to healing that occurs following superficial injury that results in no or minimal scarring. Studying the characteristics of superficial dermal injuries that heal with minimal scarring will help us identify therapeutic approaches for tissue engineering and wound healing. In addition, our ability to develop novel therapies for HTS is hampered by limitations in the available animal models used to study this disorder in vivo. We also describe a nude mouse model of transplanted human skin that develops a hypertrophic proliferative scar consistent morphologically and histologically with human HTS, which can be used to test novel treatment options for these dermal fibrotic conditions.