From standard therapies to monoclonal antibodies and immune checkpoint inhibitors - an update for reconstructive surgeons on common oncological cases.

Malignancies represent a persisting worldwide health burden. Tumor treatment is commonly based on surgical and/or non-surgical therapies. In the recent decade, novel non-surgical treatment strategies involving monoclonal antibodies (mAB) and immune checkpoint inhibitors (ICI) have been successfully incorporated into standard treatment algorithms. Such emerging therapy concepts have demonstrated improved complete remission rates and prolonged progression-free survival compared to conventional chemotherapies. However, the in-toto surgical tumor resection followed by reconstructive surgery oftentimes remains the only curative therapy. Breast cancer (BC), skin cancer (SC), head and neck cancer (HNC), and sarcoma amongst other cancer entities commonly require reconstructive surgery to restore form, aesthetics, and functionality. Understanding the basic principles, strengths, and limitations of mAB and ICI as (neo-) adjuvant therapies and treatment alternatives for resectable or unresectable tumors is paramount for optimized surgical therapy planning. Yet, there is a scarcity of studies that condense the current body of literature on mAB and ICI for BC, SC, HNC, and sarcoma. This knowledge gap may result in suboptimal treatment planning, ultimately impairing patient outcomes. Herein, we aim to summarize the current translational endeavors focusing on mAB and ICI. This line of research may serve as an evidence-based fundament to guide targeted therapy and optimize interdisciplinary anti-cancer strategies.

Cellular therapeutics and immunotherapies in wound healing - on the pulse of time?

Chronic, non-healing wounds represent a significant challenge for healthcare systems worldwide, often requiring significant human and financial resources. Chronic wounds arise from the complex interplay of underlying comorbidities, such as diabetes or vascular diseases, lifestyle factors, and genetic risk profiles which may predispose extremities to local ischemia. Injuries are further exacerbated by bacterial colonization and the formation of biofilms. Infection, consequently, perpetuates a chronic inflammatory microenvironment, preventing the progression and completion of normal wound healing. The current standard of care (SOC) for chronic wounds involves surgical debridement along with localized wound irrigation, which requires inpatient care under general anesthesia. This could be followed by, if necessary, defect coverage via a reconstructive ladder utilizing wound debridement along with skin graft, local, or free flap techniques once the wound conditions are stabilized and adequate blood supply is restored. To promote physiological wound healing, a variety of approaches have been subjected to translational research. Beyond conventional wound healing drugs and devices that currently supplement treatments, cellular and immunotherapies have emerged as promising therapeutics that can behave as tailored therapies with cell- or molecule-specific wound healing properties. However, in contrast to the clinical omnipresence of chronic wound healing disorders, there remains a shortage of studies condensing the current body of evidence on cellular therapies and immunotherapies for chronic wounds. This review provides a comprehensive exploration of current therapies, experimental approaches, and translational studies, offering insights into their efficacy and limitations. Ultimately, we hope this line of research may serve as an evidence-based foundation to guide further experimental and translational approaches and optimize patient care long-term.

Lymphadenopathy and lymph node rejection following facial vascularized composite allotransplantation.

BACKGROUND: Apart from the skin, little is known about the immunological processes in deeper tissues, which are typically not accessible to biopsy and inspection, of vascularized composite allografts (VCAs). Face transplant patients develop prominent adenopathy shortly after transplantation that resolves over time. The mechanisms underlying this process are not understood. MATERIALS AND METHODS: A retrospective cohort study was conducted on 9 patients who underwent 10 facial VCAs at the Brigham and Women's Hospital, Boston, MA, between April 2009 and July 2019. Clinical, radiological, and histological data related to lymphadenopathy of the head and neck were reviewed. RESULTS: Patients who received donor-derived lymph nodes (LNs) developed bilateral lymphadenopathy of the submental or submandibular superficial LNs. Median time of presentation was POD18 (range POD6-POM3). Notably, bilateral adenopathy of the neck was not observed in later stages of follow-up (mean follow-up, 115 months). Histology of 3 LNs showed increased histiocytes and apoptosis, with the features reminiscent of necrotizing histiocytic lymphadenitis, and B and T lymphocytes (mostly CD8 + T) admixed with CD163 + histiocytes and dendritic cells. Molecular chimerism analysis in one case showed the coexistence of donor (81%) and recipient (19%) derived lymphocytes. Granzyme B (GZMB) expression confirmed the presence of increased cytotoxic T cells in this LN sample. CONCLUSION: Our data suggested the involvement of an immunological process within the donor-derived LNs after facial allotransplantation between the recipient and donor cells. GZMB expression suggested LN rejection that can occurred independently of skin rejection. This finding supports the need to better define the role of donor-derived immune cells in the context of allograft rejection.

Understanding the Drivers of Cost and Length of Stay in a Cohort of 21,875 Patients with Severe Burn.

Burn management has significantly advanced in the past 75 years, resulting in improved mortality rates. However, there are still over one million burn victims in the United States each year, with over 3,000 burn-related deaths annually. The impacts of individual patient, hospital, and regional demographics on length of stay (LOS) and total cost have yet to be fully explored in a large nationally representative cohort. Thus, this study aimed to examine various hospital and patient characteristics using a sample of over 20,000 patients. Inpatient data from the National Inpatient Sample from 2008 to 2015 were analyzed, and only patients with an ICD-9 code for second- or third-degree burns were included. In addition, a major operating room procedure must have been indicated on the discharge summary for patients to be included in the final dataset, ensuring that only severe burns requiring complex care were analyzed. Analysis of covariance models was used to evaluate the impact of various patient, hospital, and regional variables on both LOS and cost. The study found that skin grafts and fasciotomy significantly increased the cost of hospitalization. Having burns on the face, neck, and trunk significantly increased costs for patients with second-degree burns, while burns on the trunk resulted in the longest LOS for patients with third-degree burns. Infections in the hospital and additional procedures, such as flaps and skin grafts, also led to longer stays. The study also found that the prevalence of postoperative complications, such as electrolyte imbalance, was high among patients with burn surgery.

An update on long-term mental health in eight face transplant recipients - A single center experience.

OBJECTIVE: Face transplantation is a groundbreaking and complex surgical intervention offering profound physical and psychological benefits to patients with severe facial disfigurements. This report provides an update on the long-term psychosocial outcome of eight face transplant recipients. METHOD: All transplant recipients were initially transplanted at Brigham and Women´s Hospital (Boston, USA) between 2011 and 2020 and are seen as outpatient patients at Yale New Haven Hospital (New Haven, USA). A mixed-methods approach was used to assess the psychological well-being of these patients. The Short-Form 12, Brief-COPE, EQ-VAS and CES-D were administered between October 2022 and October 2023. RESULTS: Older age of face transplant recipients was significantly and positively associated with better mental health and increased use of both emotional and instrumental support (Brief-COPE). The initial enhancement in patients' self-reported quality of life, as assessed by the EQVAS, declined on the EQ-VAS score at the last follow-up period. Similarly, an increase in depression score was observed (CES-D score) up through the last follow-up assessment. Both of the latter results, however, did not reach statistical significance. CONCLUSIONS: These results underscore the importance of ongoing psychological support throughout the long-term journey of recovery for face transplant recipients. They emphasized the need for a comprehensive, patient-centered approach that also addresses the complex psychological dimensions and contributes to our understanding of the mental health dynamics involved in face transplantation, underscoring the need for guidelines and continued research in this evolving field.

"Advancing Face Transplantation: A Critical Analysis of Revisions and Long-Term Surgical Outcomes in Ten Cases".

BACKGROUND: Face transplantation has emerged as a viable solution for reconstructing the most complex facial injuries. Prior work has demonstrated that surgical revisions are necessary to optimize outcomes. The authors' group has updated the previous report of revisions in their cohort, quantified and described which revisions were performed for functional, aesthetic, or mixed indications, and described the rationale, safety, and long-term outcomes of these revisions. METHODS: A retrospective analysis of the authors' ten face transplants was performed from April 2009 to February 2023. The patients' medical records, preoperative facial defects, and operative reports (index and secondary revisions) were reviewed. RESULTS: Nine patients were included. One patient underwent irreversible acute on chronic allograft rejection and received a second face transplant. The average number of revisions was 5.2 per patient (range, 2 to 11 procedures). The median time interval from transplantation to first revision was 4 months (range, 1 to 21 months). Median follow-up was 106 months (range 39 to 142 months). Most interventions consisted of debulking the allograft or revising the periorbital tissues. CONCLUSIONS: In the current study, we report longer term data on revision surgeries needed in face transplant recipients. Patients should expect to undergo revisions for both functional and aesthetic considerations. Although the majority of revisions are performed within two years following transplantation, revisions can be safely performed at any time point. Shared decision-making between the patient and provider team is essential in deciding which revisions are performed and when.

Ensuring Racial and Ethnic Inclusivity in Facial Vascularized Composite Allotransplantation.

Facial vascularized composite allotransplantation (fVCA) represents a valuable surgical option for reconstruction of the most devastating facial defects. There is a mounting body of evidence suggesting that healthcare disparities exist for a variety of other surgical and nonsurgical procedures. We aimed to investigate the potential existence of racial and ethnic disparities in the field of fVCA. Methods: A comprehensive literature review was conducted by the authors of this review on PubMed/MEDLINE, and Embase databases from database inception to December 1, 2022 for studies published in the English and French languages. The search terms were (1) "face" OR "facial" AND (2) "transplant" OR "VCA" OR "vascularized composite allotransplantation" OR "vascularized composite allograft" OR "graft." Results: Upon assessment of the racial and ethnic demographics of the 47 global cases of fVCA between 2005 and 2020, 36 were White, 10 were Asian, and one was Black. Sixteen of the 17 fVCA procedures performed in the United States involved White patients. The other patient self-identified as Black, equaling 6% of all US fVCA recipients. Conclusion: Our analysis showed that the ethnic and racial distribution of fVCA has not proportionally reflected the racial and ethnic demographics of the general US population, underscoring the risk of such healthcare imbalances. Although large-scale studies are needed before drawing definitive conclusions, leaders in the field should take preventive steps to avoid potential disparities. Further investigations into the factors that facilitate or prohibit access to fVCA referral and surgery will be necessary moving forward.

National Trends in Microtia Repair Cost and Hospital Length of Stay.

Microtia can have deleterious impacts on the functional, psychological, and aesthetic outcomes of affected young children. Reconstructive procedures can alleviate these negative outcomes and significantly improve the quality of life for patients; however, the cost and length of hospital stay (LOS) for such procedures and the factors that impact them have not been well-characterized. This study seeks to understand the hospital-level (institution type, size, and geographic region) and patient-level factors (race, age, and insurance status) that impact cost and LOS in patients who undergo microtia reconstructive surgery. A retrospective data analysis was conducted utilizing the National Inpatient Sample (NIS) database for the years 2008 to 2015. Inclusion criteria included patients who had an International Classification of Diseases, Ninth Revision (ICD-9) diagnostic code for microtia (744.23) as well as a procedure for microtia correction (186×/187×). A total of 714 microtia repair cases met the inclusion criteria and were sampled from the NIS database. Microtia repair cost was significantly increased on the West Coast compared with the Northeast ($34,947 versus $29,222, P =0.020), increased with patient age ($614/y, P =0.012), and gradually increased from 2008 to 2015 ($25,897-$48,985, P <0.001). Microtia LOS was significantly increased with government-controlled hospitals compared with private hospitals (1.93 versus 1.39 d, P =0.005), increased with patients on Medicaid compared with private insurance (2.33 versus 2.00 d, P =0.036), and overall decreased with patient age (-0.07 d/y, P =0.001). The results not only identify the multifactorial impacts that drive cost and LOS in microtia repair but provide insights into the financial and medical considerations patients and their families must navigate.

Pediatric Facial Burns and Consumer Products: A Nationwide Analysis.

Pediatric facial burns pose significant challenges in terms of physical, psychological, and social impacts on children. Understanding the causes of these burns is crucial for prevention and appropriate care. This study aims to provide a comprehensive analysis of causes and preventive measures related to pediatric facial burns caused by consumer products. Using data from the National Electronic Injury Surveillance System (NEISS) from 2012 to 2021, we analyzed 130,461 cases of pediatric facial burns. Common causes included household items such as cleaning supplies, hot water, kitchen appliances, and health and beauty products. Differences in burn causes were observed between genders, with boys more prone to burns from welding equipment, gasoline, and grills, while girls were more susceptible to burns from hair curling equipment, candles, and health and beauty products. The mean age of children burned by different items varied, highlighting the need for age-appropriate preventive measures. The authors discuss the importance of caregiver education, safe storage practices, supervision, and clear communication in preventing pediatric facial burns. By raising awareness of potential burn sources and implementing preventive strategies, the incidence of pediatric facial burns can be significantly reduced.

Novel Strategies in Transplantation: Genetic Engineering and Vascularized Composite Allotransplantation.

INTRODUCTION: Despite the clinical success in vascularized composite allotransplantation (VCA), systemic immunosuppression remains necessary to prevent allograft rejection. Even with potent immunosuppressive regimens (tacrolimus, mycophenolate mofetil, and steroids), most patients experience several rejection episodes, often within the same year. The risk of systemic side effects must constantly be weighed against the risk of under-immunosuppression and, thus, acute and chronic rejection. In this context, genomic editing has emerged as a potential tool to minimize the need for toxic immunosuppressive regimens and has gained attention in the fields of solid organ transplantation and xenotransplantation. This strategy may also be relevant for the future of VCA. METHODS: We discuss the topic of genetic engineering and review recent developments in this field that justify investigating tools such as clustered regularly interspaced short palindromic repeats/Cas9 in the context of VCA. RESULTS: We propose specific strategies for VCA based on the most recent gene expression data. This includes the well-known strategy of tolerance induction. Specifically, targeting the interaction between antigen-presenting cells and recipient-derived T cells by CD40 knockout may be effective. The novelty for VCA is a discovery that donor-derived T lymphocytes may play a special role in allograft rejection of facial transplants. We suggest targeting these cells prior to transplantation (e.g., by ex vivo perfusion of the transplant) by knocking out genes necessary for the long-term persistence of donor-derived immune cells in the allograft. CONCLUSION: Despite the demonstrated feasibility of VCA in recent years, continued improvements to immunomodulatory strategies using tools like clustered regularly interspaced short palindromic repeats/Cas9 could lead to the development of approaches that mitigate the limitations associated with rejection of this life-giving procedure.

Correlation between facial vascularized composite allotransplantation rejection and laboratory markers: Insights from a retrospective study of eight patients.

BACKGROUND: The field of facial vascularized composite allotransplantation (fVCA) is still new and a limited number of patients have undergone the procedure. This has led to a lack of understanding about the impact of fVCA rejection on standard laboratory markers (e.g., CBC, BMP, CRP) for the acute management of these patients. It is not clear if rejection elicits a systemic inflammatory response that influences common inflammatory markers such as WBC and CRP. A comprehensive understanding of changes in these markers could help in the management of fVCA patients in the acute setting. METHODS: The medical records of 8 fVCA patients with a total of 9 transplants were reviewed retrospectively, and data on standard laboratory values (CBC, BMP, LFTs, CRP) and vital signs were extracted. To examine the relationship between laboratory values and rejection status, linear mixed models were used to analyze the data, taking into account their longitudinal nature (repeated measures). RESULTS: A statistically significant relationship was found between the Banff grade of rejection and the relative number of basophils in the patient's blood during rejection (p = 0.005). In addition, in patients with clinical signs of rejection (e.g., facial erythema, edema) and skin biopsy showing Banff ≥ II, CRP was found to be significantly elevated (p = 0.03). The WBC count remained stable during rejection, and the relative number of neutrophils was lower at the time of rejection, indicating possible consumption at the site of rejection. CONCLUSION: During fVCA rejection, most standard laboratory parameters and vital signs appear to be stable. However, the levels of CRP and basophils were elevated during rejection, while the neutrophil count was lower. Leukocytosis can likely be used as a marker of microbial infection in fVCA patients, as WBC does not seem to increase at the time of allograft rejection.

Cellular activation pathways and interaction networks in vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.

Postoperative free flap monitoring in reconstructive surgery-man or machine?

Free tissue transfer is widely used for the reconstruction of complex tissue defects. The survival of free flaps depends on the patency and integrity of the microvascular anastomosis. Accordingly, the early detection of vascular comprise and prompt intervention are indispensable to increase flap survival rates. Such monitoring strategies are commonly integrated into the perioperative algorithm, with clinical examination still being considered the gold standard for routine free flap monitoring. Despite its widespread acceptance as state of the art, the clinical examination also has its pitfalls, such as the limited applicability in buried flaps and the risk of poor interrater agreement due to inconsistent flap (failure) appearances. To compensate for these shortcomings, a plethora of alternative monitoring tools have been proposed in recent years, each of them with inherent strengths and limitations. Given the ongoing demographic change, the number of older patients requiring free flap reconstruction, e.g., after cancer resection, is rising. Yet, age-related morphologic changes may complicate the free flap evaluation in elderly patients and delay the prompt detection of clinical signs of flap compromise. In this review, we provide an overview of currently available and employed methods for free flap monitoring, with a special focus on elderly patients and how senescence may impact standard free flap monitoring strategies.

Tolerance Induction in Vascularized Composite Allotransplantation-A Brief Review of Preclinical Models.

Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient's immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.

Realignment of Migrated Celiac Stent Graft After Branched Stent Graft Implantation Through Retrograde Cannulation of the Superior Mesenteric Artery Using a Single Vascular Access.

PURPOSE: The purpose of the study was to present an endovascular management of a type IIIc endoleak (EL) in a patient with migration of the bridging stent graft of the celiac trunk (CT) after branched aortic aneurysm repair with retrograde cannulation of the superior mesenteric artery (SMA). TECHNIQUE: The therapy was applied in a 62-year-old man who underwent a branched EVAR 2 years ago. Meanwhile, the patient was treated due to type Ia EL 6 months ago. The patient suffered in the last days from unclear hemorrhage clinically correlated with weakness. In the computed tomography angiography (CTA), an EL IIIc with a migration of the bridging stent graft from the CT branch was displayed. As vascular access, the left axillar artery was used. Due to the misaligned bridging stent graft, an antegrade cannulation was impossible, so cannulation was performed retrograde through the SMA using pancreaticoduodenal and gastroduodenal arteries. Thereafter, the EL could be repaired with bridging stent grafts. The postinterventional control showed a satisfying reconstruction without EL or embolization. CONCLUSION: Most of the complications such as type IIIc EL after complex endovascular repair can also be treated endovascularly. This sophisticated treatment requires that necessary materials and experience are available.

Antimicrobial Hypochlorous Wound Irrigation Solutions Demonstrate Lower Anti-biofilm Efficacy Against Bacterial Biofilm in a Complex in-vitro Human Plasma Biofilm Model (hpBIOM) Than Common Wound Antimicrobials.

Biofilms pose a relevant factor for wound healing impairment in chronic wounds. With 78% of all chronic wounds being affected by biofilms, research in this area is of high priority, especially since data for evidence-based selection of appropriate antimicrobials and antiseptics is scarce. Therefore, the objective of this study was to evaluate the anti-biofilm efficacy of commercially available hypochlorous wound irrigation solutions compared to established antimicrobials. Using an innovative complex in-vitro human plasma biofilm model (hpBIOM), quantitative reduction of Pseudomonas aeruginosa, Staphylococcus aureus, and Methicillin-resistant S. aureus (MRSA) biofilms by three hypochlorous irrigation solutions [two <0.08% and one 0.2% sodium hypochlorite (NaClO)] was compared to a 0.04% polyhexanide (PHMB) irrigation solution and 0.1% octenidine-dihydrochloride/phenoxyethanol (OCT/PE). Efficacy was compared to a non-challenged planktonic approach, as well as with increased substance volume over a prolonged exposure (up to 72 h). Qualitative visualization of biofilms was performed by scanning electron microscopy (SEM). Both reference agents (OCT/PE and PHMB) induced significant biofilm reductions within 72 h, whereby high volume OCT/PE even managed complete eradication of P. aeruginosa and MRSA biofilms after 72 h. The tested hypochlorous wound irrigation solutions achieved no relevant penetration and eradication of biofilms despite increased volume and exposure. Only 0.2% NaClO managed a low reduction under prolonged exposure. The results demonstrate that low-dosed hypochlorous wound irrigation solutions are significantly less effective than PHMB-based irrigation solution and OCT/PE, thus unsuitable for biofilm eradication on their own. The used complex hpBIOM thereby mimics the highly challenging clinical wound micro-environment, providing a more profound base for future clinical translation.