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Item 153. Quantification of Lymphangiogenesis in Murine Lymphedema Tail Model Using Intravital Microscopy(Wolters Kluwer, 2023-05-19) Mohan, Ganesh; Khan, Imran; Diaz, Stephanie M.; Neumann, Colby R.; Jorge, Miguel D.; Sinha, Mithun; Gordillo, Gayle M.; Sen, Chandan K.; Hassanein, Aladdin H.; Surgery, School of MedicinePURPOSE: Lymphedema is limb swelling caused by lymphatic dysfunction. It occurs in 30% of patients that undergo axillary lymph node dissection in the treatment of breast cancer. There is no cure for this disease. Understanding the mechanisms of lymphatic growth will play a pivotal role in developing therapeutic strategies against these conditions. Visualization of lymphangiogenesis and functional assessment remains a challenge. Intravital two-photon microscopy (IVM) is a powerful imaging tool for investigating various biological processes in live animals. Tissue nanotransfection technology (TNT) facilitates a direct, transcutaneous non-viral vector gene delivery using a chip with nanochannel poration in a rapid (<100ms) focused electric field. TNT was used in this study to deliver the genetic cargo in the murine tail lymphedema to assess the lymphangiogenesis. The purpose of this study is to experimentally evaluate the applicability of IVM to visualize and quantify lymphatics. METHODS: The murine tail model of lymphedema was utilized. A 3 mm full thickness skin excision and lymphatic vessel disruption was performed 20 mm from the base of the tail in twelve C57BL/6 mice. TNT was applied to the murine tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: Group I (control) was given pCMV6 (expression vector backbone alone) (n=6); Group II had pCMV6-Prox1 (n=6). Post-TNT (day 10), a 3 cm segment of murine tail was deskinned distal to the site of occlusion to optimize visualization. FITC-Dextran (2000 kD) injected intradermally at the distal tail region for lymphatic uptake. Lymphatic vessels are visualized at the second skin excision site with the Leica SP8 Confocal/Multiphoton Microscope and assessed for number of branching points to determine the newly formed lymphatics. Lymphatic vessel density was also observed by immunostaining with anti-Podoplanin antibody. RESULTS: The experimental group II exhibited increased branching points (3-fold) using filamentation analysis compared to control group I at the site of TNT treatment (n=6, p<0.05). Increased lymphatic vessel density was also observed with Podoplanin immunostaining post-TNT application. Intensity quantification of immunohistochemistry revealed greater expression of Podoplanin in Group II when compared to Group I (n=6, p<0.05). CONCLUSION: This study demonstrates a novel, powerful imaging tool for investigating lymphatic vessels in live murine tail model of lymphedema. Intravital microscopy can be utilized for functional assessment of lymphatics and visualization of lymphangiogenesis following gene-based therapy.Item ASO Author Reflections: Immediate Lymphatic Reconstruction: A Proactive Approach to Breast Cancer-Related Lymphedema(Springer, 2021-03) Cook, Julia A.; Hassanein, Aladdin H.; Surgery, School of MedicineItem Compression Therapy for HIV-Associated Kaposi Sarcoma Leg Lymphedema: Results of the Kenyan Improvised Compression for Kaposi Sarcoma Randomized Controlled Trial(American Society of Clinical Oncology, 2022) Chang, Aileen Y.; Karwa, Rakhi; Odhiambo, Haji; Were, Phelix; Fletcher, Sara L.; Tonui, Edith C.; Kohn, Michael A.; Lee, Jeannette; Chang, Di; Lensing, Shelly; Namaemba, Diana Flora; Busakhala, Naftali; Kiprono, Samson K.; Maurer, Toby; Goodrich, Suzanne; Pastakia, Sonak D.; Dermatology, School of MedicinePurpose: Evaluate the effectiveness of compression while receiving chemotherapy compared with chemotherapy alone in the treatment of HIV-associated Kaposi sarcoma (KS) lymphedema. Methods: A randomized controlled trial was conducted in a single oncology clinic in western Kenya (NCT03404297). A computer-generated randomization schedule was used to allocate treatment arms. Randomized block design was used for stratification by lymphedema stage. Participants were HIV positive adults age ≥ 18 years on antiretroviral therapy with biopsy-proven KS associated with leg lymphedema and being initiated on chemotherapy. The intervention was 10 weeks of weekly clinic-based application of two-component paste compression bandages. The primary outcome was change in the Lower Extremity Lymphedema Index (LELI) score from week 0 to week 14. The secondary outcomes were change in the Lymphedema Quality of Life measure (LYMQOL) and change in the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 score from week 0 to week 14. Blinded outcome assessments were conducted. Results: Of 30 participants randomly assigned, 25 eligible patients (chemotherapy [control], n = 13; compression plus chemotherapy [intervention], n = 12) returned at week 14. Change in LELI, LYMQOL, and EORTC QLQ-C30 scores between week 14 and week 0 did not significantly differ by arm. The mean (standard deviation) change in LELI score was -25.9 (34.6) for the control arm compared with -13.3 (29.5) for the intervention arm, P = .340. The difference (95% CI) in the change in LELI score was -12.6 (-39.3 to 14.1). Conclusion: Future studies evaluating a 14-week change in LELI for KS lymphedema should assume a standard deviation of approximately 30. Lessons learned from this pilot trial should inform the development of a larger, multicenter trial to evaluate the effectiveness of compression for KS lymphedema.Item Implementing a Locally Made Low-Cost Intervention for Wound and Lymphedema Care in Western Kenya(Elsevier, 2021) Chang, Aileen Y.; Mungai, Margaret; Coates, Sarah J.; Chao, Tiffany; Odhiambo, Haji Philip; Were, Phelix M.; Fletcher, Sara L.; Maurer, Toby; Karwa, Rakhi; Pastakia, Sonak D.; Dermatology, School of MedicineIn Western Kenya, the burden of chronic wounds and lymphedema has a significant impact on functionality and quality of life. Major barriers to provision of care include availability, affordability, and accessibility of bandages. At the Academic Model Providing Access to Healthcare, dermatologists and pharmacists collaborated to develop a 2-component compression bandage modeled after the Unna boot, using locally available materials, that is distributed through a revolving fund pharmacy network. In partnership with nursing, use of these bandages at a national referral hospital and a few county facilities has increased, but increasing utilization to an expanded catchment area is needed.Item A Murine Tail Lymphedema Model(JoVE, 2021) Hassanein, Aladdin H.; Sinha, Mithun; Neumann, Colby R.; Mohan, Ganesh; Khan, Imran; Sen, Chandan K.; Surgery, School of MedicineLymphedema is extremity swelling caused by lymphatic dysfunction. The affected limb enlarges because of accumulation of fluid, adipose, and fibrosis. There is no cure for this disease. A mouse tail model that uses a focal full thickness skin excision near the base of the tail, resulting in tail swelling, has been used to study lymphedema. However, this model may result in vascular comprise and consequent tail necrosis and early tail swelling resolution, limiting its clinical translatability. The chronic murine tail lymphedema model induces sustained lymphedema over 15 weeks and a reliable perfusion to the tail. Enhancements of the traditional murine tail lymphedema model include 1) precise full thickness excision and lymphatic clipping using a surgical microscope, 2) confirmation of post-operative arterial and venous perfusion using high resolution laser speckle, and 3) functional assessment using indocyanine green near infrared laser lymphangiography. We also use tissue nanotransfection technology (TNT) for novel non-viral, transcutaneous, focal delivery of genetic cargo to the mouse tail vasculature.Item Outcomes analysis of microsurgical physiologic lymphatic procedures for the upper extremity from the United States National Surgical Quality Improvement Program(Wiley, 2022-05) Bamba, Ravinder; Chu, Amanda; Gallegos, Jose; Herrera, Fernando A.; Hassanein, Aladdin H.; Medicine, School of MedicineINTRODUCTION: Physiologic microsurgical procedures to treat lymphedema include vascularized lymph node transfer (VLNT) and lymphovenous bypass (LVB). The purpose of this study was to assess 30-day outcomes of VLNT and LVB using the National Surgical Quality Improvement Program (NSQIP) database. METHODS: NSQIP was queried (2012-2018) for lymphatic procedures for upper extremity lymphedema after mastectomy. Prophylactic lymphatic procedures and those for lower extremity lymphedema were excluded. Outcomes were assessed for three groups: LVB, VLNT, and patients who had procedures simultaneously (VLNA+LVB). Primary outcomes measured were operative time, 30-day morbidities, and hospital length of stay. RESULTS: The study included 199 patients who had LVB (n = 43), VLNT (n = 145), or VLNT+LVB (n = 11). There was no difference in co-morbidities between the groups (p = 0.26). 30-day complication rates including unplanned reoperation (6.9% VLNT vs. 2.3% LVB) and readmission (0.69% VLNT vs. none in LVB) were not statistically significant (p = 0.54). Surgical site infection, wound complications, deep vein thromboembolism, and cardiac arrest was also similar among the three groups. Postoperative length of stay for VLNT (2.5 days± 2.3), LVB (1.9 days± 1.9), and VLNT+LVB (2.8 days± 0.3) did not differ significantly (p = 0.20). Operative time for LVB (305.4 min ± 186.7), VLNT (254 min ± 164.4), and VLNT+LVB (295.3 min ± 43.2) was not significantly different (p = 0.21). CONCLUSIONS: Our analysis of the NSQIP data revealed that VLNT and LVB are procedures with no significant difference in perioperative morbidity. Our results support that choice of VLNT versus LVB can be justifiably made per the surgeon's preference and experience as the operations have similar complication rates.Item Sarcoidosis: A rare cause of penile edema(Elsevier, 2022-07-19) Herodotou, Christopher A.; Burns, Ramzy T.; Whaley, Rumeal; Idrees, Muhammad; Mellon, Matthew J.; Urology, School of MedicineReports of penile sarcoidosis are rare in the literature. We describe the case of a male who presented with several months of distal penile swelling and progressive inability to retract the foreskin. Firm, non-tender subcutaneous nodules were palpated near the base of the penis. The patient ultimately underwent penile skin resection, partial scrotal resection, and split thickness skin graft to the penis after failing multiple conservative treatments. Pathology revealed non-caseating granulomatous lesions which in addition to CT chest findings of bilateral hilar adenopathy suggested a diagnosis of penile sarcoidosis.Item Technical Considerations to Avoid Microvascular Complications during Groin Lymph Node Free Flap Transfer(KoreaMed Synapse, 2015-09-15) Ciudad, Pedro; Orfaniotis, Georgios; Socas, Juan; Dower, Rory; Kiranantawat, Kidakorn; Nicoli, Fabio; Sapountzis, Stamatis; Maruccia, Michele; Chen, Hung-Chi; Department of Medicine, IU School of MedicineItem The Lymphedematous Limb as a Donor Site for Breast Fat Grafting(Wolters Kluwer, 2024-05-17) Ahmed, Shahnur; Mohan, Ganesh; Hulsman, Luci; Greene, Arin K.; Shaheen, Muhammad; Sinha, Mithun; Hassanein, Aladdin H.; Surgery, School of MedicineBreast cancer-related lymphedema results in chronic upper limb swelling with subcutaneous deposition of fluid and fibroadipose tissue. Morbidity includes psychosocial distress, infection, and difficulty using the extremity. Operative management includes excisional procedures such as suction-assisted lipectomy to reduce abnormal subcutaneous fibroadipose tissue to improve limb volume. Patients who have had postmastectomy breast reconstruction often benefit from fat grafting. This report introduces the concept of fat grafting the breast using the lymphedematous arm as a donor site. This technique improves the volume of the limb by removing the excess subcutaneous adipose, and at the same time reconstructs the breast without adding a donor site not related to the breast cancer-related lymphedema.Item Topical tissue nanotransfection of Prox1 is effective in the prophylactic management of lymphedema(Elsevier, 2024-01-18) Mohan, Ganesh; Khan, Imran; Neumann, Colby R.; Jorge, Miguel D.; Ahmed, Shahnur; Hulsman, Luci; Sinha, Mithun; Gordillo, Gayle M.; Sen, Chandan K.; Hassanein, Aladdin H.; Surgery, School of MedicineLymphedema is chronic limb swelling resulting from lymphatic dysfunction. There is no cure for the disease. Clinically, a preventive surgical approach called immediate lymphatic reconstruction (ILR) has gained traction. Experimental gene-based therapeutic approaches (e.g., using viral vectors) have had limited translational applicability. Tissue nanotransfection (TNT) technology uses a direct, transcutaneous nonviral vector, gene delivery using a chip with nanochannel poration in response to a rapid (<100 ms) focused electric field. The purpose of this study was to experimentally prevent lymphedema using focal delivery of a specific gene Prox1 (a master regulator of lymphangiogenesis). TNT was applied to the previously optimized lymphedematous mice tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: group I (sham) was given pCMV6 (expression vector backbone alone) and group II was treated with pCMV6-Prox1. Group II mice had decreased tail volume (47.8%) compared to sham and greater lymphatic clearance on lymphangiography. Immunohistochemistry showed greater lymphatic vessel density and RNA sequencing exhibited reduced inflammatory markers in group II compared to group I. Prox1 prophylactically delivered using TNT to the surgical site on the day of injury decreased the manifestations of lymphedema in the murine tail model compared to control.