Expanding Our Role in Headache Management: A Systematic Review and Algorithmic Approach to Surgical Management of Postcraniotomy Headache.

BACKGROUND: Chronic postcraniotomy headache (PCH) is common and debilitating. Unfortunately, the literature on this topic is sparse without clear management algorithms. Possible etiologies of PCH include nerve injury and/or entrapment, hardware, dural adhesions, or musculoskeletal injury. The purpose of this study was to present the results of both a systematic review of the literature and a single-center case series, both of which informed the development of a novel treatment algorithm that may be applied to this patient population. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we performed a systematic review of the literature, identifying articles describing the surgical management of PCH. A retrospective chart review was performed to identify patients who met the criteria for PCH treated at our institution. A patient's history and physical examination determined the etiology and management, and pain severity scores were the primary outcome measured. RESULTS: Nineteen articles encompassing 131 patients described surgical management techniques for PCH. 83 patients (63.3%) had complete resolution of pain (χ2 = 52.1, P < 0.0001). At our institution, 19 patients underwent surgical management for PCH. A significant reduction in pain scores from 7.57 to 2.16 (P < 0.001) was demonstrated, and 84 percent of patients achieved complete or significant pain reduction. CONCLUSIONS: Through a literature review and our own case series, we demonstrate that surgical management of PCH can achieve remarkable results. Plastic surgeons, with their expanding role in treating migraine and headaches, are well suited to manage these patients. We present an algorithmic approach to simplify the management of this common and debilitating condition.

"Vibration Assisted Volume Optimization Mammoplasty (VAVOM): An Alternative Approach for Large-Volume Fat Grafting to the Breast".

SUMMARY: Fat grafting has become an integral part of aesthetic and reconstructive breast surgery. However, the ideal method for harvesting and injecting the fat remains unclear. We describe an alternative approach for large-volume fat grafting in the breast, Vibration Assisted Volume Optimization Mammoplasty (VAVOM), that builds on the experience of other authors with using the power assisted liposuction machine for fat injection. We implemented this approach in 138 breasts over two years and found low rates of complications (4%). This new approach substantially reduces the time required to inject the fat graft and is simpler and faster to set up than previously described techniques. We believe VAVOM can be utilized to perform large-volume fat grafting safely and efficiently in the breast with an acceptable rate of complications.

Blue-Blood Pig Thorax Model Increases Residents' Confidence in Internal Mammary Dissection.

BACKGROUND: Preparation of the recipient vessels is a crucial step in autologous breast reconstruction, with limited opportunity for resident training intraoperatively. The Blue-Blood-infused porcine chest wall-a cadaveric pig thorax embedded in a mannequin shell, connected to a saline perfusion system-is a novel, cost-effective ($55) simulator of internal mammary artery (IMA) dissection and anastomosis intended to improve resident's comfort, safety, and expertise with all steps of this procedure. The purpose of this study was to assess the effect of the use of this chest wall model on resident's confidence in performing dissection and anastomosis of the IMA, as well as obtain resident's and faculty's perspectives on model realism and utility. METHODS: Plastic surgery residents and microsurgery faculty at the University of Wisconsin were invited to participate. One expert microsurgeon led individual training sessions and performed as the microsurgical assistant. Participants anonymously completed surveys prior to and immediately following their training session to assess their change in confidence performing the procedure, as well as their perception of model realism and utility as a formal microsurgical training tool on a five-point scale. RESULTS: Every participant saw improvement in confidence after their training session in a minimum of one of seven key procedural steps identified. Of participants who had experience with this procedure in humans, the majority rated model anatomy and performance of key procedural steps as "very" or "extremely" realistic as compared with humans. 100% of participants believed practice with this model would improve residents' ability to perform this operation in the operating room and 100% of participants would recommend this model be incorporated into the microsurgical training curriculum. CONCLUSION: The Blue-Blood porcine chest wall simulator increases trainee confidence in performing key steps of IMA dissection and anastomosis and is perceived as valuable to residents and faculty alike.

Measuring Success in Headache Surgery: A Comparison of Different Outcomes Measures.

BACKGROUND: Studies of migraine surgery have relied on quantitative, patient-reported measures like the Migraine Headache Index (MHI) and validated surveys to study the outcomes and impact of headache surgery. It is unclear whether a single metric or a combination of outcomes assessments is best suited to do so. METHODS: All patients who underwent headache surgery had an MHI calculated and completed the Headache Impact Test, the Migraine Disability Assessment Test, the Migraine-Specific Quality-of-Life Questionnaire, and an institutional ad hoc survey preoperatively and postoperatively. RESULTS: Twenty-seven patients (79%) experienced greater than or equal to 50% MHI reduction. MHI decreased significantly from a median of 210 preoperatively to 12.5 postoperatively (85%; P < 0.0001). Headache Impact Test scores improved from 67 to 61 (14%; P < 0.0001). Migraine Disability Assessment Test scores improved from 57 to 20 (67%; P = 0.0022). The Migraine-Specific Quality-of-Life Questionnaire demonstrated improvement in quality-of-life scores within all three of its domains ( P < 0.0001). The authors' ad hoc survey demonstrated that participants "strongly agreed" that (1) surgery helped their symptoms, (2) they would choose surgery again, and (3) they would recommend headache surgery to others. CONCLUSIONS: Regardless of how one measures it, headache surgery is effective. The authors demonstrate that surgery significantly improves patients' quality of life and decreases the effect of headaches on patients' functioning, but headaches can still be present to a substantial degree. The extent of improvement in migraine burden and quality of life in these patients may exceed the amount of improvement demonstrated by current measures.

Qualitative Analysis of Single-Site Headache Surgery: Is It Different From Multiple-Site Surgery?

BACKGROUND: Migraine surgery has been shown to be efficacious, but nuanced effects of surgery on pain and individuals' lives remain incompletely understood. Surgery may be performed at a single or multiple "primary" sites. The aims of this study were to investigate patient perceptions following single-site surgery and compare themes in patients undergoing single-site surgery with those from a previously published conceptual framework generated with patients undergoing multisite surgery. METHODS: Patients who underwent single-site headache surgery participated in open-ended interviews at least 1 year after surgery. Participants (n = 14) had undergone either occipital, temporal, or nasoseptal site surgery. A multidisciplinary team analyzed transcripts. Recurring themes were identified and compared and contrasted to those observed in patients who underwent multiple-site surgery (n = 15) in a previous study (Plast Reconstr Surg 2019;144(4):956-964). RESULTS: Similar recurring themes emerged from the single-site cohort, and the conceptual framework was applicable to all participants. Two new themes emerged from the single-site analysis. First, 5 of 14 participants described being "migraine-free" postoperatively, a finding not observed in the multisite group. Second, several individuals described financial benefits after surgery, via decreased prescription medication requirements, raises at work, and improved productivity. CONCLUSIONS: Single-site headache surgery appears to positively impact patients' lives in ways that support and expand upon previously published outcomes. Patients undergoing surgery at a single site may be more likely to experience a "pain-free" state, which may relate to the underlying pathophysiology of chronic headache. The effect of surgery on finances appears to be an outcome of interest to patients, which should be explored further.

Augmentation of Chicken Thigh Model with Fluorescence Imaging Allows for Real-Time, High Fidelity Assessment in Supermicrosurgery Training.

BACKGROUND: The skills required for supermicrosurgery are hard-earned and difficult to master. The University of Wisconsin "blue-blood" chicken thigh model incorporates perfusion of the thigh vessels with a blue liquid solution, allowing users to visualize flow across their anastomoses. This model has proven to be an excellent source of small vessels (down to 0.3 mm) but assessing the quality of anastomoses at this spatial scale has proven difficult. We evaluated whether fluorescent imaging with indocyanine green (ICG) in this realistic training model would enhance the assessment of supermicrosurgical anastomoses, and therefore improve real-time feedback to trainees. METHODS: Anastomoses of vessels ranging from 0.35 to 0.55mm in diameter were performed followed by the capture of white light with and without fluorescence imaging overlay during infusion of "blue-blood" and ICG. Videos were randomized and shown to seven fellowship-trained microsurgeons at the University of Wisconsin-Madison who rated each anastomosis as "patent," "not patent," or "unsure." Surgeon accuracy, uncertainty, and inter-rater agreement were measured for each imaging modality. RESULTS: Use of fluorescence significantly increased surgeon accuracy to 91% compared with 47% with white light alone (p = 0.015), decreased surgeon uncertainty to 4% compared with 41% with white light alone (p = 0.011), and improved inter-rater agreement from 53.1% with white light alone to 91.8% (p = 0.016). CONCLUSION: Augmentation of the University of Wisconsin "blue-blood" chicken thigh model with ICG fluorescence improves accuracy, decreases uncertainty, and improves inter-rater agreement when assessing supermicrosurgical anastomoses in a training setting. This improved, real-time feedback enhances this model's value as a supermicrosurgical training tool.

The Blue-Blood Porcine Chest Wall: A Novel Microsurgery Training Simulator for Internal Mammary Vessel Dissection and Anastomosis.

BACKGROUND: Preparation of the internal mammary artery (IMA) is a critical step in autologous breast reconstruction. Intraoperatively, there is limited opportunity for residents to practice this skill. Porcine models provide highly realistic simulation for vascular surgery; however, use of live laboratory pigs is expensive, inconvenient, and offers limited opportunity for repetitive training. We aimed to develop an inexpensive and effective training model for IMA preparation. This article describes creation of a novel microsurgical model using cadaveric chest walls of Wisconsin Miniature Swine embedded in a modified mannequin thorax and augmented with a blue-blood perfusion system. METHODS: Anatomic comparison: five porcine chest walls were dissected, and various anatomic measurements were made for anatomic comparison to existing human data in the literature. Model assembly: the chest wall is prepared by cannulating the proximal and distal ends of the internal mammary vessels with angiocatheters, which are then connected to the blue-blood perfusion system. The model is assembled in four layers including: (1) a mannequin thorax with a window removed to expose the first to fourth intercostal spaces, bilaterally, (2) a layer of foam simulating fat, (3) the perfused pig chest wall, and (4) a second mannequin shell placed posteriorly for support. RESULTS: The porcine chest walls are similar to humans with regards to vessel size and location. This model can be assembled quickly, with a one-time approximate cost of $55.00, and allows for six training sessions per specimen. The model allows residents to practice the key steps of IMA preparation including dissection, elevation of perichondria, and vascular anastomosis while working at a depth that closely simulates the human thorax. Continuous blue-blood perfusion provides immediate feedback on anastomosis quality. CONCLUSION: Overall, this novel model can provide inexpensive and realistic simulation of internal mammary vessel preparation and anastomosis.

Beyond the Core Suture: A New Approach to Tendon Repair.

Despite significant improvements in zone II flexor tendon repair over the last 2 decades, function-limiting complications persist. This article describes 2 novel repair techniques utilizing flexor digitorum superficialis (FDS) autografts to buttress the flexor digitorum profundus (FDP) repair site without the use of core sutures. The hypothesis being that the reclaimed FDS tendon autograft will redistribute tensile forces away from the FDP repair site, increasing overall strength and resistance to gapping in Zone II flexor tendon injuries compared with the current clinical techniques. METHODS: Two novel FDP repair methods utilizing portions of FDS have been described: (1) asymmetric repair (AR), and (2) circumferential repair. Ultimate tensile strength and cyclical testing were used to compare novel techniques to current clinical standard repairs: 2-strand (2-St), 4-strand (4-St), and 6-strand (6-St) methods. All repairs were performed in cadaveric sheep tendons (n = 10/group), by a single surgeon. RESULTS: AR and circumferential repair techniques demonstrated comparable ultimate tensile strength to 6-St repairs, with all 3 of these techniques able to tolerate significantly stronger loads than the 2-St and 4-St repairs (P < 0.0001). Cyclical testing demonstrated that AR and circumferential repair were able to withstand a significantly higher total cumulative force (P < 0.001 and P = 0.0064, respectively) than the 6-St, while only AR tolerated a significantly greater force to 2-mm gap formation (P = 0.042) than the 6-St repair. CONCLUSION: Incorporating FDS as an autologous graft for FDP repair provides at least a comparable ultimate tensile strength and a significantly greater cumulative force to failure and 2-mm gap formation than a traditional 6-St repair.

Multispecialty Microsurgical Course Utilizing the Blue-Blood Chicken Thigh Model Significantly Improves Resident Comfort, Confidence, and Attitudes in Multiple Domains.

BACKGROUND: The high level of technical skill required by microsurgical procedures has prompted the development of in vitro educational models. Current models are cost-ineffective, unrealistic, or carry ethical implications and are utilized as isolated experiences within single surgical specialties. The purpose of this study was to assess the educational and interprofessional effect of a microsurgical training course utilizing the nonliving "Blue-Blood" chicken thigh model (BBCTM) in a multidisciplinary environment. METHODS: A 10-hour course was developed integrating didactic lectures, case presentations, and one-on-one practical sessions utilizing hydrogel microvessels and the BBCTM. Pre- and postcourse surveys were administered assessing participants' self-reported comfort and confidence within fundamental microsurgical domains, assessments of the models utilized, and the effects of a multidisciplinary environment on the experience. RESULTS: A total of 19 residents attended the course on two separate occasions (n = 10 and n = 9, respectively). Respondents varied from postgraduate year-2 (PGY-2) to PGY-6+ and represented plastic and reconstructive surgery (n = 10), urology (n = 6), and otolaryngology (n = 3). On average, each participant performed 4.3 end-to-end, 1.3 end-to-side, and 0.4 coupler-assisted anastomoses. Following the course, participants felt significantly more comfortable operating a microscope and handling microsurgical instruments. They felt significantly more confident handling tissues, manipulating needles, microdissecting, performing end-to-end anastomoses, performing end-to-side anastomoses, using an anastomotic coupler, and declaring anastomoses suitable (all p < 0.05). The majority of participants believed that the use of live animals in the course would have minimally improved their learning. All but two respondents believed the course improved their awareness of the value of microsurgery in other specialties "very much" or "incredibly." CONCLUSION: A microsurgical training course utilizing nonliving models such as the "BBCTM significantly improves resident comfort and confidence in core operative domains and offers an in vivo experience without the use of live animals. Multispecialty training experiences in microsurgery are beneficial, desired, and likely underutilized.

Targeted Muscle Reinnervation in the Hand: Treatment and Prevention of Pain After Ray Amputation.

Targeted muscle reinnervation (TMR), originally developed as an experimental technique for prosthetic control, has been shown to be safe and effective for the treatment and prevention of postamputation pain. Targeted muscle reinnervation involves coaptation of residual nerve ends to nearby motor nerve branches of healthy but expendable muscles proximal to an amputation. It has been shown to prevent and reduce residual limb pain and phantom limb pain after major upper and lower extremity amputation. However, the use of this technique has not been described distal to the forearm because bioprosthetic use is not a consideration at that level. The aim of this article was to (1) present 2 cases of TMR performed in the setting of ray amputation, and (2) provide technical strategies for maximizing success and efficiency.

Major Histocompatibility Complex-Matched Arteries Have Similar Patency to Autologous Arteries in a Mauritian Cynomolgus Macaque Major Histocompatibility Complex-Defined Transplant Model.

Background Arterial bypass and interposition grafts are used routinely across multiple surgical subspecialties. Current options include both autologous and synthetic materials; however, each graft presents specific limitations. Engineering artificial small-diameter arteries with vascular cells derived from induced pluripotent stem cells could provide a useful therapeutic solution. Banking induced pluripotent stem cells from rare individuals who are homozygous for human leukocyte antigen alleles has been proposed as a strategy to facilitate economy of scale while reducing the potential for rejection of induced pluripotent stem cell-derived transplanted tissues. Currently, there is no standardized model to study transplantation of small-diameter arteries in major histocompatibility complex-defined backgrounds. Methods and Results In this study, we developed a limb-sparing nonhuman primate model to study arterial allotransplantation in the absence of immunosuppression. Our model was used to compare degrees of major histocompatibility complex matching between arterial grafts and recipient animals with long-term maintenance of patency and function. Unexpectedly, we (1) found that major histocompatibility complex partial haplomatched allografts perform as well as autologous control grafts; (2) detected little long-term immune response in even completely major histocompatibility complex mismatched allografts; and (3) observed that arterial grafts become almost completely replaced over time with recipient cells. Conclusions Given these findings, induced pluripotent stem cell-derived tissue-engineered blood vessels may prove to be promising and customizable grafts for future use by cardiac, vascular, and plastic surgeons.

Alternative Approach for Occipital Headache Surgery: The Use of a Transverse Incision and "W" Flaps.

The most commonly used approach for a greater occipital nerve decompression is through a vertical midline incision, with multiple authors reporting favorable long-term outcomes. A transverse approach to the occipital nerves has been described, yet it does not include the use of fat flaps to insulate the decompressed nerves. In this study, we describe the use of a single transverse incision with modified "W" fat flaps to decompress both the greater and lesser occipital nerves. This allows for wider exposure of the nerves without the need for an additional incision to access the lesser occipital nerve. The described technique provides increased reach and versatility of the fat flap, allowing for coverage over a longer course of the nerve and further cephalad, close to the bony skull base. In addition, the fat flaps cover the greater occipital nerve closer to its native position, as opposed to bringing the nerve into a subcutaneous position. This, theoretically, keeps the nerve in a more protected deep position and technically makes it easier to avoid any tendency for kinking the nerves while wrapping them with the fat flap. Our experience has demonstrated that this modified technique is not only safe but also efficacious in affecting a statistically significant reduction (70% improvement, P = 0.004) in migraine headache index and HIT-6 scores. This study provides further evidence that nerve decompression for headache following the principles described by Guyuron is an efficacious and reproducible procedure and that a proper nerve decompression is effective in reducing headache.

Roll, Spin, Wash, or Filter? Processing of Lipoaspirate for Autologous Fat Grafting: An Updated, Evidence-Based Review of the Literature.

BACKGROUND: The use of autologous adipose tissue harvested through liposuction techniques for soft-tissue augmentation has become commonplace among cosmetic and reconstructive surgeons alike. Despite its longstanding use in the plastic surgery community, substantial controversy remains regarding the optimal method of processing harvested lipoaspirate before grafting. This evidence-based review builds on prior examinations of the literature to evaluate both established and novel methods for lipoaspirate processing. METHODS: A comprehensive, systematic review of the literature was conducted using Ovid MEDLINE in January of 2015 to identify all relevant publications subsequent to the most recent review on this topic. Randomized controlled trials, clinical trials, and comparative studies comparing at least two of the following techniques were included: decanting, cotton gauze (Telfa) rolling, centrifugation, washing, filtration, and stromal vascular fraction isolation. RESULTS: Nine articles comparing various methods of processing human fat for autologous grafting were selected based on inclusion and exclusion criteria. Five compared established processing techniques (i.e., decanting, cotton gauze rolling, centrifugation, and washing) and four publications evaluated newer proprietary technologies, including washing, filtration, and/or methods to isolate stromal vascular fraction. CONCLUSIONS: The authors failed to find compelling evidence to advocate a single technique as the superior method for processing lipoaspirate in preparation for autologous fat grafting. A paucity of high-quality data continues to limit the clinician's ability to determine the optimal method for purifying harvested adipose tissue. Novel automated technologies hold promise, particularly for large-volume fat grafting; however, extensive additional research is required to understand their true utility and efficiency in clinical settings.

Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity.

Obesity is a major risk factor for inflammatory dermatologic diseases, including atopic dermatitis and psoriasis. In addition, recent studies have shown that obesity impairs lymphatic function. As the lymphatic system is a critical regulator of inflammatory reactions, we tested the hypothesis that obesity-induced lymphatic dysfunction is a key regulator of cutaneous hypersensitivity reactions in obese mice. We found that obese mice have impaired lymphatic function, characterized by leaky capillary lymphatics and decreased collecting vessel pumping capacity. In addition, obese mice displayed heightened dermatitis responses to inflammatory skin stimuli, resulting in both higher peak inflammation and a delayed clearance of inflammatory responses. Injection of recombinant vascular endothelial growth factor-C remarkably increased lymphangiogenesis, lymphatic function, and lymphatic endothelial cell expression of chemokine (C-C motif) ligand 21, while decreasing inflammation and expression of inducible nitrous oxide synthase. These changes resulted in considerably decreased dermatitis responses in both lean and obese mice. Taken together, our findings suggest that obesity-induced changes in the lymphatic system result in an amplified and a prolonged inflammatory response.

Regulation of inflammation and fibrosis by macrophages in lymphedema.

Lymphedema, a common complication of cancer treatment, is characterized by inflammation, fibrosis, and adipose deposition. We have previously shown that macrophage infiltration is increased in mouse models of lymphedema. Because macrophages are regulators of lymphangiogenesis and fibrosis, this study aimed to determine the role of these cells in lymphedema using depletion experiments. Matched biopsy specimens of normal and lymphedema tissues were obtained from patients with unilateral upper extremity breast cancer-related lymphedema, and macrophage accumulation was assessed using immunohistochemistry. In addition, we used a mouse tail model of lymphedema to quantify macrophage accumulation and analyze outcomes of conditional macrophage depletion. Histological analysis of clinical lymphedema biopsies revealed significantly increased macrophage infiltration. Similarly, in the mouse tail model, lymphatic injury increased the number of macrophages and favored M2 differentiation. Chronic macrophage depletion using lethally irradiated wild-type mice reconstituted with CD11b-diphtheria toxin receptor mouse bone marrow did not decrease swelling, adipose deposition, or overall inflammation. Macrophage depletion after lymphedema had become established significantly increased fibrosis and accumulation of CD4(+) cells and promoted Th2 differentiation while decreasing lymphatic transport capacity and VEGF-C expression. Our findings suggest that macrophages home to lymphedematous tissues and differentiate into the M2 phenotype. In addition, our findings suggest that macrophages have an antifibrotic role in lymphedema and either directly or indirectly regulate CD4(+) cell accumulation and Th2 differentiation. Finally, our findings suggest that lymphedema-associated macrophages are a major source of VEGF-C and that impaired macrophage responses after lymphatic injury result in decreased lymphatic function.

Decellularized Lymph Nodes as Scaffolds for Tissue Engineered Lymph Nodes.

BACKGROUND: The lymphatic system is commonly injured during cancer treatment. However, despite the morbidity of these injuries, there are currently no options for replacing damaged lymphatics. The purpose of this study was to optimize methods for decellularization of murine lymph nodes (LN) and to determine if these scaffolds can be used to tissue engineer lymph node-like structures. METHODS AND RESULTS: LNs were harvested from adult mice and subjected to various decellularization protocols. The degree of decellularization and removal of nuclear material was analyzed histologically and quantitatively using DNA isolation. In addition, we analyzed histological architecture by staining for matrix proteins. After the optimal method of decellularization was identified, decellularized constructs were implanted in the renal capsule of syngeneic or allogeneic recipient mice and analyzed for antigenicity. Finally, to determine if decellularized constructs could deliver lymphocytes to recipient animals, the matrices were repopulated with splenocytes, implanted in submuscular pockets, and harvested 14 days later. Decellularization was best accomplished with the detergent sodium dodecyl sulfate (SDS), resulting in negligible residual cellular material but maintenance of LN architecture. Implantation of decellularized LNs into syngeneic or allogeneic mice did not elicit a significant antigenic response. In addition, repopulation of decellularized LNs with splenocytes resulted in successful in vivo cellular delivery. CONCLUSIONS: We show, for the first time, that LNs can be successfully decellularized and that these matrices have preserved extracellular matrix architecture and the potential to deliver leukocytes in vivo. Future studies are needed to determine if tissue engineered lymph nodes maintain immunologic function.

Lymphaticovenous bypass decreases pathologic skin changes in upper extremity breast cancer-related lymphedema.

INTRODUCTION: Recent advances in microsurgery such as lymphaticovenous bypass (LVB) have been shown to decrease limb volumes and improve subjective symptoms in patients with lymphedema. However, to date, it remains unknown if these procedures can reverse the pathological tissue changes associated with lymphedema. Therefore, the purpose of this study was to analyze skin tissue changes in patients before and after LVB. METHODS AND RESULTS: Matched skin biopsy samples were collected from normal and lymphedematous limbs of 6 patients with unilateral breast cancer-related upper extremity lymphedema before and 6 months after LVB. Biopsy specimens were fixed and analyzed for inflammation, fibrosis, hyperkeratosis, and lymphangiogenesis. Six months following LVB, 83% of patients had symptomatic improvement in their lymphedema. Histological analysis at this time demonstrated a significant decrease in tissue CD4(+) cell inflammation in lymphedematous limb (but not normal limb) biopsies (p<0.01). These changes were associated with significantly decreased tissue fibrosis as demonstrated by decreased collagen type I deposition and TGF-ß1 expression (all p<0.01). In addition, we found a significant decrease in epidermal thickness, decreased numbers of proliferating basal keratinocytes, and decreased number of LYVE-1(+) lymphatic vessels in lymphedematous limbs after LVB. CONCLUSIONS: We have shown, for the first time, that microsurgical LVB not only improves symptomatology of lymphedema but also helps to improve pathologic changes in the skin. These findings suggest that the some of the pathologic changes of lymphedema are reversible and may be related to lymphatic fluid stasis.

Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema.

Although obesity is a major clinical risk factor for lymphedema, the mechanisms that regulate this effect remain unknown. Recent reports have demonstrated that obesity is associated with acquired lymphatic dysfunction. The purpose of this study was to determine how obesity-induced lymphatic dysfunction modulates the pathological effects of lymphatic injury in a mouse model. We used a diet-induced model of obesity in adult male C57BL/6J mice in which experimental animals were fed a high-fat diet and control animals were fed a normal chow diet for 8-10 wk. We then surgically ablated the superficial and deep lymphatics of the midportion of the tail. Six weeks postoperatively, we analyzed changes in lymphatic function, adipose deposition, inflammation, and fibrosis. We also compared responses to acute inflammatory stimuli in obese and lean mice. Compared with lean control mice, obese mice had baseline decreased lymphatic function. Lymphedema in obese mice further impaired lymphatic function and resulted in increased subcutaneous adipose deposition, increased CD45(+) and CD4(+) cell inflammation (P < 0.01), and increased fibrosis, but caused no change in the number of lymphatic vessels. Interestingly, obese mice had a significantly increased acute inflammatory reaction to croton oil application. In conclusion, obese mice have impaired lymphatic function at baseline that is amplified by lymphatic injury. This effect is associated with increased chronic inflammation, fibrosis, and adipose deposition. These findings suggest that obese patients are at higher risk for lymphedema due to impaired baseline lymphatic clearance and an increased propensity for inflammation in response to injury.

IL-6 regulates adipose deposition and homeostasis in lymphedema.

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4(+) cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4(+) inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4(+) cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.

Lymph node transplantation results in spontaneous lymphatic reconnection and restoration of lymphatic flow.

BACKGROUND: Although lymph node transplantation has been shown to improve lymphatic function, the mechanisms regulating lymphatic vessel reconnection and functional status of lymph nodes remains poorly understood. METHODS: The authors developed and used LacZ lymphatic reporter mice to examine the lineage of lymphatic vessels infiltrating transferred lymph nodes. In addition, the authors analyzed lymphatic function, expression of vascular endothelial growth factor (VEGF)-C, maintenance of T- and B-cell zone, and anatomical localization of lymphatics and high endothelial venules. RESULTS: Reporter mice were specific and highly sensitive in identifying lymphatic vessels. Lymph node transfer was associated with rapid return of lymphatic function and clearance of technetium-99 secondary to a massive infiltration of recipient mouse lymphatics and putative connections to donor lymphatics. T- and B-cell populations in the lymph node were maintained. These changes correlated with marked increases in the expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Newly formed lymphatic channels in transferred lymph nodes were in close anatomical proximity to high endothelial venules. CONCLUSIONS: Transferred lymph nodes have rapid infiltration of functional host lymphatic vessels and maintain T- and B-cell populations. This process correlates with increased endogenous expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Anatomical proximity of newly formed lymphatics and high endothelial venules supports the hypothesis that lymph node transfer can improve lymphedema by exchanges with the systemic circulation.