Vascularized composite allotransplantation (VCA) has developed over the past 20 years, resulting in promising new reconstructive prospects for extensive soft tissue defects. More than 200 VCAs have ...been performed worldwide, including five genitourinary (GU)VCAs and here we review the most recent literature in this field.
Developments in GUVCA are continuously evolving to improve patient outcomes and suggest ethical equivalency to solid organ transplant. Recent treatment options have focused on preventing GUVCA complications by acknowledging the immunogenic tissue composition of the penis to treat rejection episodes and implementing stem cell transplant to recognized the GUVCA as self. Utilizing modern, postoperative, treatments can minimize complications and although the ethical dilemma remains, the morality of performing a GUVCA has diminished. The ethical focus relic's on standardization of patient safety.
GUVCA has become an established reconstructive surgical option. The prospect of VCA's future insinuates systemization between multidisciplinary VCA programs and the United Network for Organ Sharing in efforts to endorse ethical standardization. Over the last five years, the unprecedented outcomes have shown purpose to GUVCA that initiates an obligation to help those with severe genitourinary tissue defects. Progress in immunobiology continues to evolve optimal immunosuppression drug regimens and tolerance induction protocols, highlighting potential new immunologic pathways for graft acceptance.
Vascularized composite allografts (VCA) face ischemic challenges due to their limited availability. Reperfusion following ischemia triggers oxidative stress and immune reactions, and scavenger ...molecules could mitigate ischemia-reperfusion injuries and, therefore, immune rejection. We compared two scavengers in a myocutaneous flap VCA model. In total, 18 myocutaneous flap transplants were performed in Major histocompatibility complex (MHC)-defined miniature swine. In the MATCH group (n = 9), donors and recipients had minor antigen mismatch, while the animals were fully mismatched in the MISMATCH group (n = 9). Grafts were pretreated with saline, sodium iodide (NaI), or hydrogen sulfide (H
S), stored at 4 °C for 3 h, and then transplanted. Flaps were monitored until clinical rejection without immunosuppression. In the MATCH group, flap survival did not significantly differ between the saline and hydrogen sulfide treatments (
= 0.483) but was reduced with the sodium iodide treatment (
= 0.007). In the MISMATCH group, survival was similar between the saline and hydrogen sulfide treatments (
= 0.483) but decreased with the sodium iodide treatment (
= 0.007). Rhabdomyolysis markers showed lower but non-significant levels in the experimental subgroups for both the MATCH and MISMATCH animals. This study provides insightful data for the field of antioxidant-based approaches in VCA and transplantation.
•We bioengineered rat fibroblasts to secrete a biomarker: Gaussia Luciferase.•Machine perfusion was used to engraft these genetically modified cells in rat limbs.•After transplantation we could track ...the biomarker secretion for 4 days.•It is the first step toward engraftment of biosensor cells before transplantation.•Vascularized Composite Allotransplantation would benefit from in situ cell therapy.
Transplantation of the hand or face, known as vascularized composite allotransplantation (VCA), has revolutionized reconstructive surgery. Notwithstanding, there are still several areas of improvement to mitigate immune rejection while sparing systemic adverse effects. The goal of this study was to evaluate the engraftment and viability of a genetically modified cell population pre-engrafted into a VCA transplant, to potentially act as a local biosensor to report and modify the graft in vivo. A rat fibroblast cell line genetically modified to secrete Gaussia-Luciferase (gLuc), which served as a constitutive biomarker of cells, was incorporated into a VCA to study the viability of biosensor cells in a syngeneic rat heterotopic partial hindlimb transplantation model.
Five perfusions were first performed as engineering runs to have a stable limb perfusion protocol, followed by 3 perfusions to analyze the cell engraftment during machine perfusion, and finally 4 perfusions to study in vivo persistence of the cell biosensors. Blood samples were collected to monitor gLuc secretion during perfusion and postoperatively. A time-dependent increase in gLuc secretion in the limb perfusion outflow during machine perfusion indirectly verified the presence of biosensors within the graft. After the ex vivo perfusion, VCA hindlimbs were analyzed for near infrared fluorescence emission that showed a presence of dyed engineered cells in all areas of the limbs. Postoperatively, gLuc was detectable 4 to 5 days after transplantation (W = 16, P = .02857). This study demonstrated that engineered cells could be successfully preimplanted into VCAs—an important step toward development of an in vivo biosensor platform to use in modulating acute VCA outcomes.
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OBJECTIVE:We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer.
BACKGROUND:Penis transplantation represents a new ...paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide.
METHODS:After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone.
RESULTS:Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future.
CONCLUSIONS:We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.
Vascularized composite allografts (VCAs) allow reconstruction of devastating injuries and amputations, yet require lifelong immunosuppression that is associated with significant morbidity. Induction ...of immune tolerance of VCAs would permit widespread use of these procedures. VCAs are acquired from deceased donors most likely to be
-MHC-mismatched (in contrast to living-related renal transplant donor-recipient pairs matched at one MHC haplotype). After achieving VCA tolerance in a swine model equivalent to clinical living-related renal transplants (single-haplotype MHC mismatches: e.g., "mother-daughter"/haploidentical), we tested our protocol in MHC class I, class II, and fully-MHC-mismatched pairs. Although class II mismatched swine demonstrated similar results as the haploidentical scenario (stable mixed chimerism and tolerance), our protocol failed to prevent rejection of class I and full mismatch VCAs. Here, we describe a new adapted conditioning protocol that successfully achieved tolerance across MHC class-I-mismatch barriers in swine.
Swine were treated with non-myeloablative total body and thymic irradiation two days prior to infusion of bone marrow cells from an MHC class I-mismatched donor. They also received a short-term treatment with CTLA4-Ig (Belatacept
) and anti-IL6R mAb (Tociluzimab
) and were transplanted with an osteomyocutaneous VCA from the same donor.
Stable mixed chimerism and tolerance of MHC class-I-mismatched VCAs was achieved in 3 recipients. Allograft tolerance was associated with a sustained lack of anti-donor T cell response and a concomitant expansion of double negative CD4
CD8
T cells producing IL-10.
This study demonstrates the first successful mixed chimerism-induced VCA tolerance in a large animal model across a MHC class-I-mismatch. Future studies aimed at fully-mismatched donor-recipient pairs are under investigation with this protocol.
Reconstructive techniques to repair severe tissue defects include the use of autologous fasciocutaneous flaps, which may be limited due to donor site availability or lead to complications such as ...donor site morbidity. A number of synthetic or natural dermal substitutes are in use clinically, but none have the architectural complexity needed to reconstruct deep tissue defects. The perfusion decellularization of fasciocutaneous flaps is an emerging technique that yields a scaffold with the necessary composition and vascular microarchitecture and serves as an alternative to autologous flaps. In this study, we show the perfusion decellularization of porcine fasciocutaneous flaps using sodium dodecyl sulfate (SDS) at three different concentrations, and identify that 0.2% SDS results in a decellularized flap that is efficiently cleared of its cellular material at 86%, has maintained its collagen and glycosaminoglycan content, and preserved its microvasculature architecture. We further demonstrate that the decellularized graft has the porous structure and growth factors that would facilitate repopulation with cells. Finally, we show the biocompatibility of the decellularized flap using human dermal fibroblasts, with cells migrating as deep as 150 µm into the tissue over a 7-day culture period. Overall, our results demonstrate the promise of decellularized porcine flaps as an interesting alternative for reconstructing complex soft tissue defects, circumventing the limitations of autologous skin flaps.
BACKGROUND:Local health care facilities are often unequipped to treat complex upper extremity injuries, and patients are therefore transferred to designated trauma centers. This study describes the ...characteristics of patients transferred to a Level I trauma center for hand and upper extremity injuries and to investigate the accuracy of the provided diagnosis at the time of referral.
METHODS:Adult patients transferred from outside facilities to the authors’ Level I trauma center by means of direct contract with the on-call fellow for the care of hand and upper extremity injuries were identified. Patient- and injury-related information was prospectively collected at the time of referral before patient transfer, and again following diagnostic evaluation by a hand surgeon at the authors’ institution.
RESULTS:Sixty-three patients were transferred to the authors’ hand surgery service from outside facilities after direct contact with the on-call fellow. Most patients were referred by emergency medicine physicians n = 47 (76 percent), followed by midlevel emergency department providers (physician assistant or nurse practitioner) n = 12 (19 percent) or hand surgeons n = 3 (5 percent). Six patients were transferred directly from a Level I trauma center. Twenty-one transferred patients (33 percent) had an inaccurate diagnosis at the time of referral. Factors associated with an inaccurate diagnosis included trauma level of the referring hospital and diagnoses of infection or dysvascularity.
CONCLUSIONS:The diagnostic accuracy for hand injuries transferred from outside facilities by means of provider-to-provider communication is imperfect, and some injuries are misdiagnosed. Hand surgeons should continue to improve the triage and transfer process for patients with acute hand surgery injuries.
CLINICAL QUESTION/LEVEL OF EVIDENCE:Diagnostic, IV.
The deep inferior epigastric artery perforator (DIEP) flap was first described by Koshima and Soeda in 1989 and is now well-established as the gold standard in breast reconstruction. Lately, this ...issue has been explored in the context of head and neck reconstruction, highlighting growing interest in the use of the DIEP flap beyond breast reconstruction, but its usage in other anatomical regions appears elusive. Nevertheless, DIEP flap reconstruction may be a viable choice for complex, three-dimensional head and neck deformities while upholding the criteria of minimal donor site morbidity, according to a recent review. To determine whether the DIEP flap may be used successfully in other types of reconstruction, we conducted a review on the use, applications, and outcomes of the DIEP flap in non-breast reconstruction. This is, as far as we are aware, the first comprehensive analysis of all applications of the DIEP flap other than for breast reconstruction.
A literature review was performed using PubMed to include all relevant articles in English or French published up to February 2022. Keywords included "DIEP flap" and "deep inferior epigastric perforator flap".
A total of 1,299 articles were identified with 105 on the use of the DIEP flap in non-breast reconstruction. This suggests increasing recognition of the DIEP flap as a feasible option for reconstruction of most anatomical regions, especially in lower limb and head and neck reconstruction, followed by gynecological reconstruction. The DIEP flap was also utilized in the reconstruction of upper limb, thigh and hip defects. Less commonly, it has been used for penoscrotal, groin, sternal, buttock and abdomen reconstruction.
The scientific body of evidence showed the robustness and versatility of the DIEP flap in non-breast reconstruction, with its relative pros and cons at different anatomical regions.
Previous vascularized composite allograft (VCA) studies from our laboratory have shown that topical FK506 delivery in non-human primates (NHPs) was limited by inadequate dermal penetration and ...rejection persisted. Herein, we report the first utilization of FK506 via subcutaneously implanted discs to mitigate VCA rejection in NHPs.
Full major histocompatibility complex (MHC)-mismatched NHP pairs underwent partial-face VCA and FK506 disc implantation along the suture line. All allotransplants were maintained post-operatively for two months on the FK506 discs, methylprednisolone, mycophenolate mofetil, and supplemented with intramuscular FK506 if necessary. Group 1 (n=4) was used for optimization of the implant, while Group 2 (n=3) underwent delayed bone marrow transplantation (DBMT) after two months. VCA skin biopsies and peripheral blood samples were obtained for serial assessment of rejection and mixed chimerism by histopathology and flow cytometry respectively.
In Group 1, two technical failures occurred. Of the remaining two NHPs, one developed supratherapeutic levels of FK506 (50-120 ng/mL) and had to be euthanized on postoperative day (POD) 12. Reformulation of the implant resulted in stable FK506 levels (20-30 ng/mL) up to POD12 when further intramuscular (IM) FK506 injections were necessitated. In Group 2, two NHPs survived to undergo conditioning and one successfully developed chimerism at 2-3 weeks post-DBMT (96-97% granulocytes and 7-11% lymphocytes of recipient-origin). However, all three NHPs had to be terminated from study at POD64, 77 and 86 due to underlying post-transplant lymphoproliferative disorder. All VCAs remained rejection-free up to study endpoint otherwise.
This study shows preliminary results of local FK506 implants in potentially mitigating VCA acute rejection for tolerance protocols based on mixed chimerism approach.
Purpose
Mammoplasty removes random samples of breast tissue from asymptomatic women providing a unique method for evaluating background prevalence of breast pathology in normal population. Our goal ...was to identify the rate of atypical breast lesions and cancers in women of various ages in the largest mammoplasty cohort reported to date.
Methods
We analyzed pathologic reports from patients undergoing bilateral mammoplasty, using natural language processing algorithm, verified by human review. Patients with a prior history of breast cancer or atypia were excluded.
Results
A total of 4775 patients were deemed eligible. Median age was 40 (range 13–86) and was higher in patients with any incidental finding compared to patients with normal reports (52 vs. 39 years,
p
= 0.0001). Pathological findings were detected in 7.06% (337) of procedures. Benign high-risk lesions were found in 299 patients (6.26%). Invasive carcinoma and ductal carcinoma in situ were detected in 15 (0.31%) and 23 (0.48%) patients, respectively. The rate of atypias and cancers increased with age.
Conclusion
The overall rate of abnormal findings in asymptomatic patients undergoing mammoplasty was 7.06%, increasing with age. As these results are based on random sample of breast tissue, they likely underestimate the prevalence of abnormal findings in asymptomatic women.
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