Sumeet S. Teotia

Cardiac xenotransplantation: progress toward the clinic.

Background. Animal organs could satisfy the demand for solid organ transplants, which currently exceeds the limited human donor supply. Hyperacute rejection, the initial immune barrier to successful xenotransplantation, has been overcome with pig donors transgenic for human complement regulatory proteins. Delayed xenograft rejection, thought to be mediated by anti-pig antibodies predominantly to Gal antigens, is currently regarded as the major barrier to successful xenotransplantation. A median graft survival of 90 days in the life-supporting position is considered a reasonable initial standard for consideration of entry to the clinic. Methods. A series of 10 heterotopic heart transplants from CD46 transgenic pigs to baboons was completed. Immunosuppression consisted of splenectomy, Rituximab (Anti-CD20), tacrolimus, sirolimus, corticosteroids, and TPC. Thymoglobulin (Rabbit Anti-Thymocyte Globulin) was used to treat putative rejection episodes. Results. Median graft survival was 76 days (range 56–113 days, n=9). Only three grafts were lost to rejection. The remaining grafts lost were due to recipient mortality with baboon cytomegalovirus (BCMV) being the major cause (n=4). No cellular infiltrates were present as a manifestation of rejection. Three hearts showed chronic graft vasculopathy. Conclusions. The median survival of 76 days in this group of heterotopic porcine-to-baboon cardiac xenografts represents a major advance over the median 27-day survival reported in the literature. Cellular rejection may not constitute a direct major barrier to xenotransplantation. A median survival of 90 days may be achievable with better control of BCMV infection. If further studies in the orthotopic position replicate these outcomes, criteria considered appropriate for clinical application of cardiac xenotransplantation would be approached.

Increased immunosuppression, not anticoagulation, extends cardiac xenograft survival

Background. Cardiac xenograft function is lost due to delayed xenograft rejection (DXR) characterized by microvascular thrombosis and myocardial necrosis. The cause of DXR is unknown but may result from thrombosis induced by antibody-mediated activation of endothelial cells and/or by incompatibilities in thromboregulatory interactions. Methods. To examine these issues, a series (Groups 1–6) of previous transgenic CD46 pig-to-baboon heterotopic cardiac transplants were reanalyzed for baseline immunosuppressive levels, graft survival and infectious complications with and without systemic anticoagulation. Groups 1–4 received low dose tacrolimus and sirolimus maintenance therapy, with splenectomy, anti-CD20 and daily α-Gal polymer. Group 1 recipients received no anticoagulation. Groups 2–4 were anticoagulated with aspirin and Plavix, Lovenox, or Coumadin, respectively. Group 5 was treated with Lovenox and high dose tacrolimus and sirolimus maintenance therapy. Group 6 recipients received no postoperative anticoagulation but the same immunosuppression as group 5. Results. Median survival (15–22 days) within groups 1–4 was not significantly different. At rejection all tissues exhibited microvascular thrombosis, coagulative necrosis and similar levels of platelet and fibrin deposition. Groups 5 and 6 median survival (76 days) was significantly increased compared to groups 1–4. There was no significant difference in median survival between Lovenox treated recipients (68 days) and anticoagulant free recipients (96 days). Rejected tissues showed vascular antibody deposition, microvascular thrombosis, and myocyte necrosis. Conclusion. Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.

Warfarin or low-molecular-weight heparin therapy does not prolong pig-to-primate cardiac xenograft function

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low‐molecular‐weight heparin (LMWH) anti‐coagulation on xenograft function using a heterotopic pig‐to‐primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti‐CD20 and TPC, an α‐galactosyl‐polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anti‐coagulant drugs. The median duration of xenograft function was 20 days (range 3–62 days), 18 days (range 5–109 days) and 15 days (range 4–53 days) in Groups 1 to 3 respectively. Anti‐coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti‐factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti‐coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anti‐coagulant strategies to achieve long‐term xenograft function cannot be excluded.

Achieving Low Cleft Palate Fistula Rates: Surgical Results and Techniques

Objectives To prospectively evaluate and reduce fistula rate after primary cleft palate repair in an academic setting. Methods After noting an institutional palate fistula rate of 35.8%, when a majority of palatoplasties were performed using the Furlow double-opposing Z-plasty, the decision was made to re-evaluate the surgical techniques used for palate repair. As part of our re-evaluation, Furlow and von Langenbeck repairs were limited to clefts less than 8 mm in width. Wider clefts were repaired early in the series with Veau-Wardill-Kilner and later with Bardach two-flap palatoplasties. Half of each palate repair was performed by the residents. Setting Multidisciplinary follow-up was obtained at the University of North Carolina Craniofacial Center. Results A palate fistula was noted in 2 (1.6%) out of 126 cleft palate repairs (both fistulas were located at the anterior hard palate). A split uvula was identified in 2 of 59 patients where the status of the uvula was reported (3.4%). Conclusion This study summarizes one of the lowest overall fistula rates reported in the literature. In a tertiary-care academic setting, plastic surgery residents can actively contribute to palatoplasty with a very low fistula rate. Technical keys to achieving low fistula rate include skeletonization of the vascular pedicle for medialization of the mucoperiosteal flaps, aggressive posterior repositioning of the levator muscle, and meticulous two-layer mattress-suture closure. We recommend Furlow repair for narrower clefts (less than 8 mm wide at the posterior border of the hard palate) and the Bardach two-flap palatoplasty for wider clefts.

Do Progressive Tension Sutures Really Decrease Complications in Abdominoplasty

The purpose of this study is to evaluate the efficacy of progressive tension sutures (PTS) in preventing or reducing seroma formation and local wound complications in patients undergoing abdominoplasty. Forty-nine patients who underwent abdominoplasty procedures with the use of PTS were retrospectively compared with a historical control group of 54 patients who underwent standard abdominoplasty. Primary outcomes measured were seroma formation and local wound complications, including hypertrophic scar formation, umbilical distortion, and wound necrosis. Secondary outcomes were all other complications and time to drain removal. Overall complication rates and local wound complication rates were significantly reduced with the addition of PTS to abdominoplasty. Seroma formation and the time to drain removal were reduced in the PTS group, but the findings were not statistically significant.

Prevention, detection, and management of early bacterial and fungal infections in a preclinical cardiac xenotransplantation model that achieves prolonged survival

Abstract:  Background:  We analyzed bacterial and fungal infectious complications in a cohort of 16 consecutive experiments with the longest surviving cardiac xenografts to date. Methods: Transgenic, porcine‐to‐baboon, heterotopic (abdomen) cardiac xenotransplantation was performed in 16 consecutive experiments, using rapamycin, tacrolimus, corticosteroids, anti‐CD20 monoclonal antibody, and an alpha‐Gal‐PEG polymer, as immunosuppression. Prophylactic anti‐microbials included i.v. trimethoprim/sulfamethoxazole, oral ganciclovir/valganciclovir, and oral itraconazole. An episode of bacterial infection was defined as a positive blood and/or wound culture with: leukocytosis, fever >101.5°F, and/or clinical deterioration. Results: Mean graft survival was 71 ± 29 days; the longest was 113 days. There were 23 episodes of bacterial infection; 14 resolved with treatment. The mean time to the first episode of infection was 44 ± 21 days (n = 12). Eight of 16 deaths were due to infection: two bacterial‐only, two cytomegalovirus (CMV) only, four both bacterial and CMV, and none fungal. The frequency of infection was 1, 2.8, and 1.8 episodes/100 survival days, respectively, for animals whose grafts survived for 30 to 59, 60 to 89, and >90 days. CMV infection (reviewed in detail in a separate communications) was due to baboon CMV, and was associated with low serum levels of ganciclovir. Conclusion: In a cardiac xenograft model that achieved prolonged (>3 months) survival, bacteremia was common, but usually reversible, and fungal infection was prevented with prophylaxis. The level of immunosuppression required to achieve clinically meaningful xenograft survival is associated with a level of bacterial and fungal infectious complications that is manageable and similar to the early clinical experiences in human transplantation. Further research will determine if the viral infectious complications observed in these experiments can be reduced by optimizing blood levels of anti‐viral prophylaxis and monitoring viral polymerase chain reaction levels.

STARplasty for reconstruction of the burned web space: Introduction of an alternative technique for the correction of dorsal neosyndactyly

Introduction:Significant hand burns frequently result in dorsal neosyndactyly, despite appropriate wound care, excision/grafting, and occupational therapy. Patients often develop limited abduction, tethered flexion/extension, intrinsic tightness, and inversion of the web space. We present a new technique for neosyndactyly release: the STARplasty (Syndactyly Treatment After Release), named after the appearance of the reconstructed web. Methods:We performed a retrospective review of 25 patients who underwent 66 web space reconstructions by a single surgeon, from January 2002 to December 2003. The STARplasty was developed prior to the study period, with the following goals: to use local tissue, negate the need for a skin graft, and permit early range of motion. Combined with longitudinal, transverse, and oblique releases, STARplasty uses a single volar flap, harvested from each sidewall of both proximal phalanges, with 30-degree corners. STARplasty simultaneously deepens and widens the web space while correcting the angle of inclination. Results:Sixteen patients (mean age: 34 years; range: 3–62 years) underwent a total of 33 STARplasties, an average of 37 months after burn injury. Mean area resurfaced per web was 5.2 cm2, which contrasts with the 33 non-STARplasty reconstructions, which were used to resurface a mean area of 19.4 cm2 (P < 0.05) and included 5-flap z-plasties (17), full-thickness skin graft (10), 2-flap z-plasties (3), and advancement flaps (3). No complications occurred in the STARplasty group, including infection, flap loss, dehiscence, nerve injury, or recurrent contracture. All patients had improved function (mean follow-up: 6.7 months; range: 1-18 months). Conclusions:STARplasty is a new, safe, and efficacious technique to correct dorsal neosyndactyly and reconstruct the web space after burn injury.

Take Two and Text Me in the Morning: Optimizing Clinical Time with a Short Messaging System

Background: Despite the widespread availability and convenience of short messaging systems, there has been limited adoption of this technology into the medical setting. Resistance may be attributable, in part, to the perceived lack of clinical benefit, privacy concerns, and a lack of physician compensation. This study evaluates the impact of a short messaging system clinical protocol between surgeons and patients. The endpoints evaluated were number of clinic visits, telephone calls, and days to surgical drain removal. Methods: Retrospective review identified 102 procedure-matched patients who underwent breast reconstruction for an oncologic diagnosis. A short messaging system protocol was routinely used by one of the two study surgeons. Data collected included demographics, pathologic findings, procedures, complications, clinic visits, clinic telephone calls, days until drain removal, and episode of drain removal. Results: The two groups were well-matched for age, procedure, race, complications, and pathologic findings. Patients in the short messaging system clinical protocol had statistically fewer clinic visits within the first 30 days (p = 0.0004) and 90 days (p = 0.017) postoperatively. There were fewer clinic telephone calls in the messaging group (p = 0.0002). The short messaging system protocol allowed for fewer days until drain removal (9.67 ± 0 .41 versus 12.45 ± 1.02, p = 0.013). Patients in the messaging group were more likely to undergo drain removal at the first clinic visit. Conclusions: Benefits of a short messaging system protocol included reduced number of clinic visits, fewer overall days of drain requirement, and increased efficiency of clinic visits. Concerns regarding physician privacy, compensation, and time need to be addressed before further application of this technology. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

No-drain DIEP Flap Donor-site Closure Using Barbed Progressive Tension Sutures.

Background: The use of progressive tension sutures has been shown to be comparable to the use of abdominal drains in abdominoplasty. However, the use of barbed progressive tension sutures (B-PTSs) in deep inferior epigastric artery perforator (DIEP) flap donor-site closure has not been investigated. Methods: A retrospective chart review was performed on patients with DIEP flap reconstruction in a 3-year period at 2 institutions by 2 surgeons. Patients were compared by method of DIEP donor-site closure. Group 1 had barbed running progressive tension sutures without drain placement. Group 2 had interrupted progressive tension closure with abdominal drain placement (PTS-AD). Group 3 had closure with only abdominal drain placement (AD). Data collected included demographics, perioperative data, and postoperative outcomes. Results: Seventy-five patients underwent DIEP reconstruction (25 B-PTS, 25 PTS-AD, and 25 AD). Patient characteristics—age, body mass index, comorbidities, smoking status, and chemotherapy—were not significantly different between groups. Rate of seroma was 1.3% (B-PTS = 0%, PTS-AD = 4%, AD = 0%), wound dehiscence 16% (B-PTS = 8%, PTS-AD = 16%, AD = 24%), and umbilical necrosis 5.3% (B-PTS = 0%, PTS-AD = 0%, AD = 16%). No hematomas were observed in any patients. No statistically significant difference was found between complication rates across groups. Conclusions: Use of B-PTSs for abdominal closure after DIEP flap harvest can obviate the need for abdominal drains. Complication rates following this technique are not significantly different from closure using progressive tension suture and abdominal drain placement. This practice can prevent the use of abdominal drains, which can promote patient mobility, increase independence upon discharge, and contribute to patient satisfaction.

The Profunda Artery Perforator Flap: Investigating the Perforasome Using Three-Dimensional Computed Tomographic Angiography.

Background: The profunda artery perforator flap has been emerging as an alternative method of autologous breast reconstruction. This flap uses upper posterior thigh tissue. The profunda artery perforator perforasome is investigated using three-dimensional computed tomographic angiography. Methods: Ten cadaveric thighs were dissected centered over the profunda artery perforator. The perforator was injected with contrast medium and the flap was then subjected to computed tomographic scanning using a GE Lightspeed 16-slice scanner. The three-dimensional images were viewed, and measurements were obtained using Aquarius software, including horizontal and vertical extensions of the flap and areas of perfusion. Clinical examples are presented. Results: A profunda artery perforator (occasionally two) was consistently found in the upper medial thigh region, posterior to the gracilis muscle. The area of vascularity shown by the spread of contrast extends inferiorly beyond the usual lower border of the profunda artery perforator flap, which is usually 7 cm wide. In injected cadaveric flaps, the mean horizontal dimension was 16.7 cm and the mean vertical dimension was 16.5 cm. The mean area perfused was 8812 cm2. Conclusions: The profunda artery perforator flap is a vascularly sound flap, and is a good option for autologous breast reconstruction. Advantages include a reliable pedicle, no position changes required, and possibly an improved donor-site contour from a thigh lift. It is an excellent alternative to abdominally based free flaps and can also be used in conjunction with other flaps for further volume enhancement.