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Small numbers of CD4+ T cells can induce development of lymphedema

Ly, Catherine L; Cuzzone, Daniel A; Kataru, Raghu P; Mehrara, Babak J
BACKGROUND:CD4 T cells have been implicated in the pathology of lymphedema. Interestingly, however, there have been case reports of lymphedema development in patients with low levels of CD4 T cells due to immunosuppression. In this study, we sought to delineate the effect of relative CD4 T cell deficiency on the development of lymphedema in a mouse model. METHODS:A mouse model of relative CD4 T cell deficiency was created through lethal total body irradiation of wild-type (WT) mice that then underwent bone marrow transplantation with progenitors harvested from CD4 knockout (CD4KO) mice (WT/CD4KO). Irradiated CD4KO mice reconstituted with WT mouse-derived progenitors (CD4KO/WT), as well as unirradiated CD4KO and WT mice were used as controls. All mice underwent tail skin and lymphatic excision to induce lymphedema and analysis was performed six weeks later. RESULTS:WT/CD4KO chimeras were not protected from developing lymphedema. Despite a global deficit in CD4 T cells, these mice had swelling, fibrosis, inflammation, and impaired lymphatic transport function indistinguishable from that in WT and CD4KO/WT mice. In contrast, unirradiated CD4KO mice had no features of lymphedema after lymphatic injury. CONCLUSIONS:Relatively few numbers of bone marrow and peripheral CD4 T cells are sufficient to induce the development of lymphedema. These findings suggest that lymphatic injury results in expansion of CD4 T cell populations in lymphedematous tissues.
PMID: 30601329
ISSN: 1529-4242
CID: 3680852

Outcome Analysis of Metacarpal and Phalangeal Fixation Techniques at Bellevue Hospital

Reformat, Derek Daniel; Nores, Gabriela García; Lam, Gretl; Cuzzone, Daniel; Hill, John Bradford; Muresan, Horatiu; Thanik, Vishal
PURPOSE/OBJECTIVE:Phalangeal fractures represent a significant portion of upper extremity injuries but are not well studied as a single entity. We define our approach at a level 1 trauma center and determine whether plating or lag screws (ie, rigid fixation) have superior functional outcomes compared with Kirschner wire fixation for phalangeal or metacarpal fractures. METHODS:We performed a systematic review of all surgically managed hand fracture cases at Bellevue Hospital during 2012 and 2013. Demographics, type of fixation, length of operation, period of immobilization, range of motion, time to return to work, and complications including reoperation were noted. Comparisons were assessed for significance using Student t tests and Fisher exact test (P < 0.05 considered significant). RESULTS:One hundred ninety-two fractures (158 patients) were treated and followed for an average of 113 days. Rigid fixation was used for 17 (19%) of 90 metacarpal fractures and 5 (5%) of 102 phalangeal fractures. Operative times were significantly shorter (59 vs 135 minutes, 84 vs 149 minutes), and period of immobilization was longer (37 vs 15 days, 34 vs 18 days) when Kirschner wires were used for metacarpal and phalangeal fractures, respectively (P > 0.05). Total active motion and return to work were similar regardless of type of intervention in both fracture types. No patients treated with rigid fixation required reoperation. CONCLUSIONS:To our best knowledge, this is the first review to study phalangeal fractures concurrently but also separately from metacarpal fractures. Despite shorter periods of immobilization, rigid fixation does not appear to lead to improved total active motion or time to return to work.
PMID: 30067527
ISSN: 1536-3708
CID: 3217462

CD4+ T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema

García Nores, Gabriela D; Ly, Catherine L; Cuzzone, Daniel A; Kataru, Raghu P; Hespe, Geoffrey E; Torrisi, Jeremy S; Huang, Jung Ju; Gardenier, Jason C; Savetsky, Ira L; Nitti, Matthew D; Yu, Jessie Z; Rehal, Sonia; Mehrara, Babak J
T cell-mediated responses have been implicated in the development of fibrosis, impaired lymphangiogenesis, and lymphatic dysfunction in secondary lymphedema. Here we show that CD4+ T cells are necessary for lymphedema pathogenesis by utilizing adoptive transfer techniques in CD4 knockout mice that have undergone tail skin and lymphatic excision or popliteal lymph node dissection. We also demonstrate that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells such as dendritic cells. CD4+ T cell activation is associated with differentiation into a mixed T helper type 1 and 2 phenotype, as well as upregulation of adhesion molecules and chemokines that promote migration to the skin. Most importantly, we find that blocking T cell release from lymph nodes using a sphingosine-1-phosphate receptor modulator prevents lymphedema, suggesting that this approach may have clinical utility.
PMID: 29773802
ISSN: 2041-1723
CID: 3120812

Optimizing Safety of Iliac Bone Harvest Using an Acumed Drill: A Simulated Radiographic Study of 100 Patients

Stranix, John T; Cuzzone, Daniel; Ly, Catherine; Topilow, Nicole; Runyan, Christopher M; Ream, Justin; Flores, Roberto L
OBJECTIVE: To determine the potential risk of visceral injury during Acumed drill iliac crest cancellous bone graft harvest. DESIGN: Radiographic iliac crest anatomic analysis with simulated drill course to measure cancellous bone available for harvest and proximity of vulnerable pelvic structures. SETTING: Single institution, tertiary care university hospital. PATIENTS AND PARTICIPANTS: One hundred pelvic computed tomography scans performed on children 8 to 12 years old without traumatic or neoplastic pathology. INTERVENTIONS: Radiographic simulation of Acumed drill course within iliac bone. MAIN OUTCOME MEASURES: (1) Potential for pelvic visceral injury. (2) Volume of cancellous bone safely available for harvest. RESULTS: Superior and medial cortical thickness at the reference point remained stable across age groups; however, lateral cortical thickness increased with age (3.13 to 3.74 mm, P < .001). Cancellous bone width increased with age at all depths measured (P < .001). Through radiographic simulation, the drill could reach the bowel in 4% of cases and only through gross deviation (>30 degrees ) from the plane of the ilium. There were no cases of simulated bowel perforation within 3 cm of the reference point. The maximum cancellous volume safely harvested increased with age: 24 cc in 8-year-olds to 36 cc in 12-year-olds (P < .001). CONCLUSIONS: Acumed assisted iliac crest bone graft harvest is a safe technique in which substantial amount of cancellous bone can be obtained. The low risk of bowel perforation can be further minimized by limiting the depth of drill bit penetration to less than 3 cm.
PMID: 27632764
ISSN: 1545-1569
CID: 2779922

Inhibition of Inflammation and iNOS Improves Lymphatic Function in Obesity

Torrisi, Jeremy S; Hespe, Geoffrey E; Cuzzone, Daniel A; Savetsky, Ira L; Nitti, Matthew D; Gardenier, Jason C; Nores, Gabriela D Garcia; Jowhar, Dawit; Kataru, Raghu P; Mehrara, Babak J
Although recent studies have shown that obesity decreases lymphatic function, the cellular mechanisms regulating this response remain unknown. In the current study, we show that obesity results in perilymphatic accumulation of inflammatory cells and that local inhibition of this response with topical tacrolimus, an inhibitor of T cell differentiation, increases lymphatic vessel density, decreases perilymphatic iNOS expression, increases lymphatic vessel pumping frequency, and restores lymphatic clearance of interstitial fluid to normal levels. Although treatment of obese mice with 1400W, a selective inhibitor of iNOS, also improved lymphatic collecting vessel contractile function, it did not completely reverse lymphatic defects. Mice deficient in CD4(+) cells fed a high fat diet also gained weight relative to controls but were protected from lymphatic dysfunction. Taken together, our findings suggest that obesity-mediated lymphatic dysfunction is regulated by perilymphatic accumulation of inflammatory cells and that T cell inflammatory responses are necessary to initiate this effect.
PMID: 26796537
ISSN: 2045-2322
CID: 2043652

Lymphatic Function Regulates Contact Hypersensitivity Dermatitis in Obesity

Savetsky, Ira L; Albano, Nicholas J; Cuzzone, Daniel A; Gardenier, Jason C; Torrisi, Jeremy S; Nores, Gabriela D G; Nitti, Matthew D; Hespe, Geoffrey E; Nelson, Tyler S; Kataru, Raghu P; Brandon Dixon, J; Mehrara, Babak J
PMID: 26176761
ISSN: 1523-1747
CID: 1675322

Decellularized Lymph Nodes as Scaffolds for Tissue Engineered Lymph Nodes

Cuzzone, Daniel A; Albano, Nicholas J; Aschen, Seth Z; Ghanta, Swapna; Mehrara, Babak J
Abstract 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.
PMID: 25144673
ISSN: 1539-6851
CID: 1142542

Lymphaticovenous Bypass Decreases Pathologic Skin Changes in Upper Extremity Breast Cancer-Related Lymphedema

Torrisi, Jeremy S; Joseph, Walter J; Ghanta, Swapna; Cuzzone, Daniel A; Albano, Nicholas J; Savetsky, Ira L; Gardenier, Jason C; Skoracki, Roman; Chang, David; Mehrara, Babak J
Abstract 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-beta1 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.
PMID: 25521197
ISSN: 1539-6851
CID: 1411342

Macrophages Regulate Tissue Fibrosis in Lymphedema [Meeting Abstract]

Ghanta, Swapna; Cuzzone, Daniel A; Albano, Nicholas J; Savetsky, Ira L; Gardenier, Jason C; Torrisi, Jeremy S; Joseph, Walter J; Mehrara, Babak J
ISSN: 1879-1190
CID: 1458062

Sterile inflammation after lymph node transfer improves lymphatic function and regeneration

Joseph, Walter J; Aschen, Seth; Ghanta, Swapna; Cuzzone, Daniel; Albano, Nicholas; Gardenier, Jason; Savetsky, Ira; Torrisi, Jeremy; Mehrara, Babak J
BACKGROUND: The aim of this study was to determine whether sterile inflammatory reactions can serve as a physiologic means of augmenting lymphangiogenesis in transplanted lymph nodes using a murine model. METHODS: The authors used their previously reported model of lymph node transfer to study the effect of sterile inflammation on lymphatic regeneration. Mice were divided into three groups: group 1 (controls) underwent lymphadenectomy followed by immediate lymph node transplantation without inflammation; group 2 (inflammation before transfer) underwent transplantation with lymph nodes harvested from donor animals in which a sterile inflammatory reaction was induced in the ipsilateral donor limb; and group 3 (inflammation after transfer) underwent transplantation with lymph nodes and then inflammation was induced in the ipsilateral limb. Lymphatic function, lymphangiogenesis, and lymph node histology were examined 28 days after transplantation and compared with those of normal lymph nodes. RESULTS: Animals that had sterile inflammation after transplantation (group 3) had significantly improved lymphatic function (>2-fold increase) on lympho scintigraphy, increased perinodal lymphangiogenesis, and functional lymphatics compared with the groups with no inflammation and inflammation before transplantation (p < 0.01). Inflammation after transplantation was associated with a more normal lymph node architecture, expansion of B-cell zones, and decreased percentage of T cells compared with the other experimental groups. CONCLUSIONS: Sterile inflammation is a potent method of augmenting lymphatic function and lymphangiogenesis after lymph node transplantation and is associated with maintenance of lymph node architecture. Induction of inflammation after transplantation is the most effective method and promotes maintenance of normal lymph node B- and T-cell architecture.
PMID: 25028818
ISSN: 1529-4242
CID: 1075172