Peter Than, MD

Abstract

Combined heart-liver transplant is an emerging option for patients with indications for heart transplantation and otherwise prohibitive hepatic dysfunction. Heart-liver transplantation is particularly relevant for patients with single ventricle physiology who often develop Fontan-associated liver disease and fibrosis. While only performed at a limited number of centers, several approaches to combined heart-liver transplantation have been described. The en bloc technique offers several potential advantages over the traditional sequential technique. Specifically, en bloc heart-liver transplantation may allow improved hemodynamics, decreased bleeding, reduced liver allograft ischemic time, and may result in reduced rates of graft dysfunction. Here we describe our center's en bloc heart-liver procurement technique in detail, with the aim of allowing broader use and standardization of this technique. Supplemental Visual Abstract; http://links.lww.com/TP/C147.

View details for DOI 10.1097/TP.0000000000003697

View details for PubMedID 33606485

View details for Web of Science ID 000574027003241

View details for Web of Science ID 000618872101233

View details for Web of Science ID 000618872101227

View details for Web of Science ID 000618872101244

View details for Web of Science ID 000505634300187

Abstract

After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using vascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access be used to deliver therapeutic agents using the tissue flap as a vehicle? Such delivery may be more efficient than systemic treatment, in terms of oncological outcomes. The cytokine interferon gamma (IFNgamma) has antitumor effects, but systemic toxicity that could be circumvented if its effect can be localized by delivery of the IFNgamma gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNgamma and exerts anti-tumor effects. In a rat model of loco-regional recurrence (LRR) using both MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector (AAV) encoding IFNgamma. The therapeutic reconstruction released IFNgamma at the LRR site and eliminated cancer cells, significantly decreased tumor burden (P<0.05), and increased survival by 33% (P<0.05) compared to sham reconstruction. Mechanistically, localized IFNgamma immunotherapy stimulated M1 macrophages to target cancer cells within the regional confines of the modified tumor environment. This concept of therapeutic breast reconstruction using ex vivo gene therapy of autologous tissue offers a new application for immunotherapy in breast cancer with a dual therapeutic effect of both reconstructing the ablative defect and delivering local adjuvant immunotherapy.

View details for DOI 10.1158/1535-7163.MCT-19-0315

View details for PubMedID 31658961

View details for Web of Science ID 000457809000016

Abstract

Fibroproliferative disorders result in excessive scar formation, are associated with high morbidity, and cost billions of dollars every year. Of these, keloid disease presents a particularly challenging clinical problem because the cutaneous scars progress beyond the original site of injury. Altered mechanotransduction has been implicated in keloid development, but the mechanisms governing scar progression into the surrounding tissue remain unknown. The role of mechanotransduction in keloids is further complicated by the differential mechanical properties of keloids and the surrounding skin.The authors used human mechanical testing, finite element modeling, and immunohistologic analyses of human specimens to clarify the complex interplay of mechanical stress, strain, and stiffness in keloid scar progression.Changes in human position (i.e., standing, sitting, and supine) are correlated to dynamic changes in local stress/strain distribution, particularly in regions with a predilection for keloids. Keloids are composed of stiff tissue, which displays a fibrotic phenotype with relatively low proliferation. In contrast, the soft skin surrounding keloids is exposed to high mechanical strain that correlates with increased expression of the caveolin-1/rho signaling via rho kinase mechanotransduction pathway and elevated inflammation and proliferation, which may lead to keloid progression.The authors conclude that changes in human position are strongly correlated with mechanical loading of the predilection sites, which leads to increased mechanical strain in the peripheral tissue surrounding keloids. Furthermore, increased mechanical strain in the peripheral tissue, which is the site of keloid progression, was correlated with aberrant expression of caveolin-1/ROCK signaling pathway. These findings suggest a novel mechanism for keloid progression.

View details for DOI 10.1097/PRS.0000000000005717

View details for PubMedID 31246819

View details for DOI 10.21037/ls.2018.10.10

Abstract

Sutureless microvascular anastomosis has great translational potential to simplify microvascular surgery, shorten operative times, and improve clinical outcomes. The authors developed a transient thermoreversible microvascular stent using a poloxamer to maintain vessel lumen patency before application of commercially available adhesives to seal the anastomosis instead of sutures. Despite technical success, human application necessitates bovine serum albumin removal from existing formulations; rapid poloxamer transition between states; and increased stiffness for reliable, reproducible, and precise microvascular approximation.Two commercially available poloxamers were used in this study (P407 and P188). After removing bovine serum albumin, each poloxamer was tested at varying concentrations either alone or in combination to determine the optimal preparation for sutureless microvascular anastomosis. Transition temperature and formulation stiffness were tested in vitro by rheometry, with the most promising combinations tested in an established in vivo model.Increasing poloxamer concentration resulted in an increase in stiffness and decrease in transition temperature. Pure P188 without bovine serum albumin, dissolved in phosphate-buffered saline to a 45% concentration, demonstrated desirable rheologic behavior, with precise gel transition and increased gel stiffness compared with our previous formulation of 17% P407 (96 kPa versus 10 kPa). These characteristics were optimal for microsurgical intravascular use, offering surgical precision and control between liquid and solid states, depending on the surgically controlled local temperature.Use of 45% P188 without bovine serum albumin demonstrated optimal rheologic and translational properties as a microvascular stent for sutureless anastomosis. Rapid transition, increased stiffness, and safety profile demonstrate safe translational application for human clinical trials.

View details for DOI 10.1097/01.prs.0000475774.37267.3f

View details for PubMedID 26818289

View details for DOI 10.1016/j.epsc.2015.12.005

View details for Web of Science ID 000370155600005

View details for DOI 10.1016/j.jamcollsurg.2015.07.372

View details for Web of Science ID 000361119700327

View details for Web of Science ID 000370124201434

View details for DOI 10.1016/j.jamcollsurg.2014.07.339

View details for Web of Science ID 000342420900299

View details for PubMedID 25028858

View details for Web of Science ID 000332835400102

View details for Web of Science ID 000332835400048

View details for DOI 10.1016/j.jamcollsurg.2014.07.212