Graft Rejection Research Articles

Estimation of Immunosuppressants by Liquid Chromatography Tandem Mass Spectrometry in Clinical Laboratories

Immunosuppressive drugs or Immunosuppressants have contributed significantly to the success of organ transplantation by preventing graft rejection. They inhibit the activity of the immune system by reducing the proliferation and function of cells associated with immune reactions.

Effectiveness of Autodermoplasty in Combination with Injection of Autological Stromal-Vascular Cell Fraction in Treatment of Deep Burns

Introduction. The use of autologous stromal-vascular cell fraction of adipose tissue seems to be one of the promising technologies to increase the effectiveness of skin grafting and other skin restoration options in burnt patients. The main regenerative component of the stromal-vascular fraction are mesenchymal stem cells, which have a high reparative potential and low immunogenicity.The aim of the study was to increase the effectiveness of surgical treatment of patients with skin burns through the injection of autological stromal-vascular cell fraction of the adipose tissue.Materials and methods. The study was conducted as part of a prospective, open, randomized study involving 61 patients with extensive skin burns treated in burn centers Dzhanelidze Saint-Petersburg Research Institute of Emergency Medicine and Vishnevsky National Medical Research Center of Surgery, Ministry of Health of Russia, in 2021-2023. Cells of the stromal-vascular fraction of the adipose tissue were obtained mechanically and enzymatically. The prepared cell suspension was introduced into the granulation tissue during skin grafting with split autodermal grafts having a high perforation coefficient. During the study, planimetric parameters, as well as the results of histological and immunohistochemical tests, were assessed. The obtained findings were processed using generally accepted algorithms of variation and descriptive statistics. The alternative hypothesis was accepted at p0.05.Results. The proposed technique of autologous stromal-vascular cell fraction of the adipose tissue with simultaneous autodermoplasty with a split perforated graft allowed reducing the time of perforating cell epithelization by 28% (p0.05), the time of final engraftment by 11% (p0.05), the frequency of infectious complications in the postoperative period by 20% (p0.05), as well as the frequency of lysis and rejection reactions by 15% (p0.05). As stated, the introduction of an autologous stromal-vascular fraction during skin grafting resulted in early relief of the inflammatory reaction in the area of a deep burn wound, the fact being supported by clinical, cytological, histological and immunohistochemical tests.Conclusion. The use of cells from the stromal-vascular fraction of the adipose tissue can significantly increase the effectiveness of surgical treatment of patients with extensive skin burns. The proposed technique to obtain and apply the stromal-vascular fraction of the adipose tissue at the stage of autodermoplasty can be introduced into clinical practice in both burn centers and surgical/trauma departments, since it does not require special equipment.

T cell responsiveness to IL-10 defines the immunomodulatory effect of costimulation blockade via anti-CD154 and impacts transplant survival.

Costimulation blockade (CoB)-based immunotherapy is a promising alternative to immunosuppression for transplant recipients; however, the current limited understanding of the factors that impact its efficacy restrains its clinical applicability. In this context, pro- and anti-inflammatory cytokines are being recognized as having an impact on T cell activation beyond effector differentiation. This study aims at elucidating the impact of direct IL-10 signaling in T cells on CoB outcomes. We used a full-mismatch skin transplantation model where recipients had a T cell-restricted expression of a dominant negative IL-10 receptor (10R-DN), alongside anti-CD154 as CoB therapy. Unlike wild-type recipients, 10R-DN mice failed to benefit from CoB. This accelerated graft rejection correlated with increased accumulation of T cells producing TNF-α, IFN-γ, and IL-17. In vitro experiments indicated that while lack of IL-10 signaling did not change the ability of anti-CD154 to modulate alloreactive T cell proliferation, the absence of this pathway heightened T H 1 effector cell differentiation. Furthermore, deficiency of IL-10 signaling in T cells impaired Treg induction, a hallmark of anti-CD154 therapy. Overall, these findings unveil an important and novel role of IL-10 signaling in T cells that defines the success of CoB therapies and identifies a target pathway for obtaining robust immunoregulation.

Feasibility Study the Effectiveness of Self-care Promoting Program on Self-care Behavioral and Clinical Outcomes in People with Corneal Transplantation: A Quasi-experiment Study

Corneal transplantation is the most effective treatment for visual impairment caused by corneal blindness and can improve patients’ quality of vision. However, pre- and post-operative self-care is necessary to reduce the risk of complications and graft rejection. This one-group, quasi-experimental design with repeated measures aimed to determine the feasibility and effectiveness of self-care promoting programs on self-care behavior, anxiety, and clinical outcomes in individuals with corneal transplantation. Thirty participants who met the inclusion criteria were purposively recruited from a corneal excellence center in Bangkok, Thailand, from October 2021 to August 2022. The data collection instruments included the Demographic and Health Data Forms, the Self-Care Behavior Questionnaire, and the Self-Rating Anxiety Scale. The data were analyzed using descriptive statistics, paired t-tests, and Friedman and Wilcoxon signed-rank tests. The program was found to be feasible, with all participants able to attend for 30 days postoperation. In terms of effectiveness, participants demonstrated improved self-care behavior and reduced anxiety compared to pre-program levels. Visual acuity also showed improvement 30 days postoperation, with 83.3% of participants having a clear corneal graft. These findings are significant for nursing practice, as they suggest that this program could be a promising tool for enhancing self-care behavior in individuals undergoing corneal transplantation. Nurses could potentially use this program to promote self-care behavior, alleviate anxiety, and enhance clinical outcomes. However, further research with randomized control is necessary before widespread implementation can be recommended.

Topical tacrolimus for high-risk corneal transplantation: a randomized, clinical trial

BackgroundThe prevalence of rejection is 10–30% in penetrating keratoplasty (PKP) case, and the rate is higher in cases of high-risk patients. Although using topical corticosteroids is a standard method for management the rejection of post-PKP patients, it may not be sufficiently potent in high-risk patients. Topical administration of tacrolimus (TAC) may be effective in suppression rejection after corneal transplantation. This study aimed to investigate the efficacy and safety of topical TAC in high-risk PKP patients in Japan.MethodsThis study was a single centre, single-blinded, randomized controlled trial. Patients with a history of PKP, graft rejection, atopic dermatitis, or deep corneal neovascularisation who underwent PKP were enrolled. They were randomly assigned to receive 0.1% TAC ophthalmic suspension or artificial tear (AT) up to week 52 after surgery. All participants received 0.1% betamethasone up to week 13 after surgery then they received 0.1% fluorometholone up to week 52. The incidence of immunological rejection during the observation period was the main outcome measure in this study.ResultsThirty patients were enrolled in this study, and 12 eyes in the TAC group and 13 eyes in the AT group completed the study, respectively. Five out of 30 patients discontinued participation after providing informed consent. No serious adverse effects were developed in patients who received 0.1% TAC ophthalmic suspension. No rejection episodes occurred in the TAC group, while one eye in the AT group had rejection. Graft clarity, best spectacle-corrected visual acuity, intraocular pressure, and corneal endothelial cell density were not significantly different between the TAC and AT groups.ConclusionOur results demonstrated that good tolerability of 0.1% TAC ophthalmic suspension. However, we failed to demonstrate its efficacy in preventing immunological rejection in high-risk patients undergoing PKP.Trial registrationThis study was first registered in the University Hospital Medical Information Network (UMIN000029669, Date of registration: November 1, 2017). With the enforcement of the Clinical Trial Act in Japan, the study re-registered in the Japan Registry of Clinical Trials (jRCTs031180342, Date of registration: March 18, 2019).

Challenges and opportunities for designing clinical trials for antibody mediated rejection.

Significant progress has been made in kidney transplantation, with 1-year graft survival nearing 95%. However, long-term allograft survival remains suboptimal, with a 10-year overall graft survival rate of only 53.6% for deceased donor transplant recipients. Chronic active antibody-mediated rejection (ABMR) is a leading cause of death-censored graft loss, yet no therapy has demonstrated efficacy in large, randomized trials, despite substantial investment from pharmaceutical companies. Several clinical trials aimed to treat chronic ABMR in the past decade have yielded disappointing results or were prematurely terminated, attributed to factors including incomplete understanding of disease mechanisms, heterogeneous patient populations with comorbidities, slow disease progression, and limited patient numbers. This review aims to discuss opportunities for improving retrospective and prospective studies of ABMR, focusing on addressing heterogeneity, outcome measurement, and strategies to enhance patient enrollment to inform study design, data collection, and reporting.

Granulomatous Tubulointerstitial Nephritis in a Kidney Allograft: Treatment with Interleukin-6 Receptor Antagonist Stabilises Kidney Function

Granulomatous tubulointerstitial nephritis (GTIN) attributed to early onset sarcoidosis is an ultrarare finding in an allograft kidney biopsy. We present the case of a young man with allograft dysfunction who had GTIN upon biopsy. We performed a thorough case review based on recovered records from early childhood and reassessed genetic testing results. We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). This suppressed his inflammatory disease and stabilised kidney function. We performed a literature review related to the emerging role of IL-6 pathway blockade in kidney transplantation. We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials.

Gene therapy for rare haematological and neurometabolic paediatric diseases

Nowadays, gene therapy hast the potential to cure an increasingly greater number of monogenic inherited disorders with absent or limited treatment options, and radically change their natural history. Hematopoietic stem cells (HSCs) represent one of the preferred targets for gene therapy, as genetic modification of multipotent cells ensures a permanent correction of the progeny. Gene-corrected HSCs and their progeny can also be used as cell vehicles to deliver molecules into the circulation and tissues, including the central nervous system or the skeleton. Major successes of this approach have been achieved in the field of monogenic blood disorders and neurometabolic diseases and several medicinal products have recently reached the stage of marketing approval by the EMA based on safety and efficacy data collected over more than 10 years of clinical trials. Gene therapy for these severe pathologies offers undeniable advantages over the sole alternative therapy of allogeneic transplantation because it can be applied to every patient, even when no matched HLA donor is available, reducing mortality and complications related to allogeneic transplantation, such as graft-versus-host disease, graft rejection, organ toxicity, and infections. Additionally, in neurometabolic diseases, gene therapy allows supra-physiological expression of the transgene, consequently producing supra-normal levels of the missing enzyme, providing a greater clinical benefit compared to allogeneic transplantation. Despite these remarkable achievements, several challenges remain for HSPC gene therapy regarding access to treatment and its sustainability for the future.

Evaluating the Clinical Relevance of Antibodies against Non-Human Leukocyte Antigen in Kidney Transplantation.

Introduction: Kidney transplantation is the preferred modality of kidney replacement therapy for eligible patients with end-stage kidney disease (ESKD), given that it has been found to reduce mortality rates, improve quality of life, and is cost-effective compared to dialysis. Recent advancements in human leukocyte antigen (HLA) typing and donor-specific antibody (DSA) detection have helped to reduce the risk of rejection, but antibody-mediated rejection (AMR) can still occur without DSA. Previous studies suggest that rejection can be attributed to antibodies against Non-Human Leucocyte Antigens (non-HLAs). We aimed to acquire further understanding of the prevalence and distribution of non-HLA antibodies in our local population and attempt to correlate these findings with graft outcomes, as well as assess whether non-HLA antibodies can be utilized to determine graft impairment and dysfunction. Methods: We conducted a retrospective study involving kidney transplant recipients between January 2010 and December 2020. All included individuals were aged over 18 and underwent kidney-alone transplants; were ABO- and HLA-compatible; and were matched at A, B, and DR loci (mismatch 0:0:0). HLA testing was negative at the time of transplantation. The samples from both cases of early graft rejection and the control group were tested for non-HLA antibodies using One Lambda LABScreenTM, Autoantibody kit groups 1, 2, and 3, as well as the Immucor LIFECODES non-HLA autoantibody assay. Results: A total of 850 kidney transplant recipients were included, in which 12 patients experienced early graft rejection within the first month post transplant and 18 patients who did not experience graft rejection were selected as study controls. Our study reported no correlation between the total burden of non-HLA antibodies and early rejection, most likely as the result of a small sample size. Nevertheless, a sub-analysis revealed that specific high-frequency pre-transplant non-HLA antibodies such as GSTT, CXCL11, CXCL10, and HNR, detected by LIFECODES, were associated with rejection (Fisher's exact test with Bonferroni correction, p < 0.001). Most pre-transplant non-HLA antibody levels were reduced after transplantation, which was attributed to immunosuppression. Conclusion: The 'high frequency' non-HLA antibodies displayed an association with graft rejection, though the overall associations between the burden of non-HLA antibodies and rejection episodes remain inconclusive. Further work is needed to establish the rebound phenomenon of non-HLA antibodies, the development of de novo non-HLA antibodies in the long run, and their implications on graft survival.

Pattern of CYP3A5 and MDR-1 single nucleotide polymorphism and its impact on Tacrolimus levels and clinical outcomes in living renal allograft recipient

Abstract Introduction Renal transplant is best form of renal replacement therapy. Most favored immunosuppression includes Tacrolimus, mycophenolate mofetil and steroids. Tacrolimus has narrow therapeutic index and requires therapeutic drug monitoring (TDM). However, there is wide variation in tacrolimus level with weight based fixed dosage regimens. This variability is due to polymorphism of major pathways of metabolism ie CYP3A5 and MDR1 genes. Fast metabolizer require higher dosage and slow metabolizer require lower dosage. Genotype based dosing strategy may be useful to achieve early therapeutic level and reduce infections and rejections. Methodology 160 transplant patients at tertiary care hospital in India were included in this study from 2016 to 2018. Genetic polymorphism analysis in CYP3A5 and MDR1 gene was carried out at time of transplant. All patients were given a fixed weight-based dosage of Tacrolimus. Data was analyzed in relation to genotype polymorphism. Results and discussion 69.2% of Wild variants of CYP 3A5 (Fast metabolizers) have low initial tacrolimus levels. 51.5% of Homo variants (Slow metabolizers) have high initial tac levels. However, all variants achieve optimum tacrolimus levels at same time (mean 12.4 days). There were higher number of infections among slow metabolizers. Conclusion A fixed dosing regimen with TDM result in high and low initial tacrolimus levels in slow and fast metabolizers respectively and more infections in slow metabolizers. However, graft rejections being fewer in number, were not different. A larger sample with genotype based dosing is required to test such a strategy.

Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications

BackgroundMesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. MethodsExtensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. ResultsThe most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. ConclusionMesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.

Nanoparticle-hydrogel composite as dual-drug delivery system for the potential application of corneal graft rejection

Immune rejection remains the major cause of corneal graft failure. Immunosuppressants (such as rapamycin; RAPA) adjunctive to antibiotics (such as levofloxacin hydrochloride; Lev) are a clinical mainstay after corneal grafts but suffer from poor ocular bioavailability associated with severe side effects. In this study, we fabricated a Lev@RAPA micelle loaded cationic peptide-based hydrogel (NapFFKK) as a dual-drug delivery system by integrating RAPA micelles with Lev into a cationic NapFFKK hydrogel to potentially reduced the risk of corneal graft rejection. The properties of the resulting hydrogels were characterized using transmission electronmicroscopy and rheometer. Lev@RAPA micelles loaded NapFFKK hydrogel provided sustained in vitro drug release without compromising their inherent pharmacological activities. Topical instillation of Lev@RAPA micelles loaded NapFFKK hydrogel resulted in the great ocular tolerance and extended precorneal retention over 60 min, thus significantly enhancing the ocular bioavailability of both Lev and RAPA. Overall, such dual-drug delivery system might be a promising formulation for the suppression of corneal graft failure.

Droplet digital PCR based analysis of chimerism using a panel of Indel markers

Cell identity, a fundamental concept in biology, emerges from the interplay of gene expressions, cellular functions, and genomic fingerprints. Chimerism refers to the presence of two genetically distinct types of cells within an individual. Monitoring of chimerism is an important tool to evaluate the evolution of engraftment after transplant and to detect the relapse of the underlying hematological neoplasm or the occurrence of graft rejection. Also, continuous monitoring is an essential tool that can provide guidance for early therapeutic intervention. Digital droplet PCR (ddPCR) is a promising alternative to the standard quantitative PCR to assess the chimerism below 1% due to an excellent performance in the assessment of small amounts of specific targets in a complex biological sample. Here, we describe the development of a panel of ddPCR based assays for chimeric analysis. We found a group of 25 indels showing a good discrimination power when tested with artificial mixtures of DNA samples.

A local drug delivery system prolongs graft survival by dampening T cell infiltration and neutrophil extracellular trap formation in vascularized composite allografts.

The standard treatment for preventing rejection in vascularized composite allotransplantation (VCA) currently relies on systemic immunosuppression, which exposes the host to well-known side effects. Locally administered immunosuppression strategies have shown promising results to bypass this hurdle. Nevertheless, their progress has been slow, partially attributed to a limited understanding of the essential mechanisms underlying graft rejection. Recent discoveries highlight the crucial involvement of innate immune components, such as neutrophil extracellular traps (NETs), in organ transplantation. Here we aimed to prolong graft survival through a tacrolimus-based drug delivery system and to understand the role of NETs in VCA graft rejection. To prevent off-target toxicity and promote graft survival, we tested a locally administered tacrolimus-loaded on-demand drug delivery system (TGMS-TAC) in a multiple MHC-mismatched porcine VCA model. Off-target toxicity was assessed in tissue and blood. Graft rejection was evaluated macroscopically while the complement system, T cells, neutrophils and NETs were analyzed in graft tissues by immunofluorescence and/or western blot. Plasmatic levels of inflammatory cytokines were measured using a Luminex magnetic-bead porcine panel, and NETs were measured in plasma and tissue using DNA-MPO ELISA. Lastly, to evaluate the effect of tacrolimus on NET formation, NETs were induced in-vitro in porcine and human peripheral neutrophils following incubation with tacrolimus. Repeated intra-graft administrations of TGMS-TAC minimized systemic toxicity and prolonged graft survival. Nevertheless, signs of rejection were observed at endpoint. Systemically, there were no increases in cytokine levels, complement anaphylatoxins, T-cell subpopulations, or neutrophils during rejection. Yet, tissue analysis showed local infiltration of T cells and neutrophils, together with neutrophil extracellular traps (NETs) in rejected grafts. Interestingly, intra-graft administration of tacrolimus contributed to a reduction in both T-cellular infiltration and NETs. In fact, in-vitro NETosis assessment showed a 62-84% reduction in NETs after stimulated neutrophils were treated with tacrolimus. Our data indicate that the proposed local delivery of immunosuppression avoids off-target toxicity while prolonging graft survival in a multiple MHC-mismatch VCA model. Furthermore, NETs are found to play a role in graft rejection and could therefore be a potential innovative therapeutic target.

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.

Pancreatic islet transplantation: current advances and challenges.

Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.

Risk factors and crucial prognostic indicators of mortality in liver transplant recipients with bloodstream infections: A comprehensives study of 1049 consecutive liver transplants over an 11-year period

BackgroundLiver transplantation (LT) is a pivotal treatment for end-stage liver disease. However, bloodstream infections (BSI) in the post-operative period present a significant threat to patient survival. This study aims to identify risk factors for post-LT BSI and crucial prognostic indicators for mortality among affected patients. MethodsWe conducted a retrospective study of adults diagnosed with end-stage liver disease who underwent their initial LT between 2010 and 2021. Those who developed BSI post-LT during the same hospital admission were classified into the BSI group. ResultsIn this cohort of 1049 patients, 89 (8.4%) developed BSI post-LT, while 960 (91.5%) did not contract any infection. Among the BSI cases, 17 (19.1%) patients died. The average time to BSI onset was 48 days, with 46% occurring within the first month post-LT. Of the 123 isolated microorganisms, 97 (78.8%) were gram-negative bacteria. BSI patients had significantly longer stays in the intensive care unit and hospital compared to non-infected patients. The 90-day and in-hospital mortality rates for recipients with BSI were significantly higher than those without infections. Multivariate analysis indicated heightened BSI risk in patients with blood loss >3000 mL during LT (odds ratio [OR] 2.128), re-operation within 30 days (OR 2.341), post-LT bile leakage (OR 3.536), and graft rejection (OR 2.194). Additionally, chronic kidney disease (OR 6.288), each 1000 mL increase in intraoperative blood loss (OR 1.147) significantly raised mortality risk in BSI patients, whereas each 0.1 mg/dL increase in albumin levels correlated with a lower risk of death from BSI (OR 0.810). ConclusionsThis study underscores the need for careful monitoring and management in the post-LT period, especially for patients at higher risk of BSI. It also suggests that serum albumin levels could serve as a valuable prognostic indicator for outcomes in LT recipients experiencing BSI.

Transbronchial Cryobiopsy Versus Transbronchial Forceps Biopsy for Acute Cellular Rejection Detection in Lung Transplantation: A Meta-Analysis

BackgroundTransbronchial cryobiopsy (TBCB) provides larger tissue samples and improved sampling depth, but its role in diagnosing acute cellular rejection (ACR) in lung transplant patients is unclear due to limitations in existing studies. To address this, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of TBCB. MethodsA thorough literature review was conducted to evaluate TBCB in post-lung transplant surveillance, assessing the quality of studies and conducting a meta-analysis comparing diagnostic yields of TBCB and transbronchial forceps biopsy (TBFB), as well as evaluating procedural complications. ResultsOur meta-analysis, incorporating 11 studies with a total of 915 patients, showed that TBCB had a diagnostic rate of 38.27% (225/588) for ACR post-lung transplantation, notably higher than the 35.65% (251/704) for TBFB. The inverse-variance weighted odds ratio was calculated at 2.32 (95% confidence interval: 1.24–4.32; p=0.008). Funnel plot analysis indicated no major publication bias. Meta-analysis of 6 studies demonstrated that TBCB, compared to TBFB, significantly increased the diagnostic rate for chronic rejection post-transplantation (25.00% vs 10.93%, p=0.005). Our meta-analysis comparing the safety of TBCB and TBFB in post-lung transplant surveillance found no significant differences in moderate to severe bleeding (5.99% vs 6.31%, p=0.98), or pneumothorax incidence (3.90% vs 3.29%, p=0.75). ConclusionsOur study indicates that TBCB may enhance the diagnosis of acute and chronic rejection post-lung transplantation with a safety profile comparable to TBFB. Further research and the development of standardized procedures are warranted to ensure the safe and effective application of TBCB in broader clinical practice.

Magnetic sphincter augmentation: A promising alternative to fundoplication for preserving lung function and protecting against chronic lung transplant rejection

BackgroundEarly laparoscopic fundoplication (LF) has been shown to slow lung function decline in chronic lung disease (CLD) patients and lung transplant (LTx) recipients. Magnetic sphincter augmentation (MSA) has emerged as an effective minimally invasive alternative to LF for the treatment of GERD. We evaluate the safety and efficacy of MSA compared to LF for GERD in CLD and LTx. MethodsA retrospective review identified CLD and LTx patients undergoing LF or MSA for GERD. Primary outcome was change in percent predicted FEV1. Secondary outcomes were 30d morbidity, mortality, operative time, and length of stay (LOS). Results77 patients met inclusion criteria, 45 (58.5 %) were LTx recipients. 35 (45.5 %) underwent Nissen, 23 (29.9 %) underwent Toupet, and 19 (24.7 %) underwent MSA. Average age was 54.2 years, 54.5 % were female, and average BMI at ARS was 24.9 kg/m2. Median FEV1 % change between pre-ARS and post-ARS was 0 % with no significant differences between groups. MSA had faster operative times at 50.5 min than Nissen (83.5 min, p = 0.002) and Toupet (72.6 min, p = 0.003) and shorter LOS at 0.8 days than Nissen (3.7 days, p = 0.002) and Toupet (2.1 days, p = 0.0008). MSA and Nissen had higher reintervention rates than Toupet, though this was not statistically significant. There were no differences in 30-day morbidities or 30-day ED visits between groups. There were no mortalities. ConclusionMSA is an advantageous alternative to LF in the CLD and LTx population with stabilization of percent predicted FEV1, equivalent safety profile, shorter operative times, and shorter length of hospital stay.

Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future.

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.