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Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS.

A minimal diffusion barrier is key to the pulmonary gas exchange. In alveolar capillary dysplasia (ACD), a rare genetically driven disease of early infancy, this crucial fibrovascular interface is compromised while the underlying pathophysiology is insufficiently understood. Recent in-depth analyses of vascular alterations in adult lung disease encouraged researchers to extend these studies to ACD and compare the changes of the microvasculature. Lung tissue samples of children with ACD (n= 12), adults with non-specific interstitial pneumonia (n= 12), and controls (n= 20) were studied using transmission electron microscopy, single-gene sequencing, immunostaining, exome sequencing, and broad transcriptome profiling. In ACD, pulmonary capillary basement membranes were hypertrophied, thickened, and multilamellated. Transcriptome profiling revealed increased CDH5, COL4A1, COL15A1, PTK2B, and FN1and decreased VITexpression, confirmed by immunohistochemistry. In contrast, non-specific interstitial pneumonia samples showed a regular basement membrane architecture with preserved VIT expression but also increased COL15A1+vessels. This study provides insight into the ultrastructure and pathophysiology of ACD. The lack of normally developed lung capillaries appeared to cause a replacement by COL15A1+vessels, a mechanism recently described in interstitial lung disease. The VITloss and FN1overexpression might contribute to the unique appearance of basement membranes in ACD. Future studies are needed to explore the therapeutic potential of down-regulating the expression of FN1and balancing VIT deficiency.

Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B-cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain. As proof-of-concept, CORA receptors based on HLA-A*02 were developed. In co-cultures with anti-HLA-A*02 B-cell lines, CORA-Ts were specifically activated, released pro-inflammatory mediators, and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLA-A*02 antibody release. Significant reduction of growth of an anti-HLA-A*02 B-cell line could be confirmed using an in vivomouse model. Modification of the CORA receptor effectively abrogated T-cell binding, thereby avoiding T-cell sensitization. Additionally, using CRISPR/Cas9-mediated knockout of the FKBP12gene, CORA-Ts were able to resist immunosuppressive treatment with tacrolimus, thereby allowing high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically eliminate alloreactive, anti-HLA B cells, thus selectively preventing anti-HLA antibody release even under immunosuppressive conditions. This suggests CORA-Ts as potent approach to combat AMR and improve long-term graft survival in SOT patients while preserving their overall B-cell immunity.

Die Transplantationsmedizin in Deutschland ist klar strukturiert und verbindlich geregelt. Zur Stärkung der Organspende wurden die rechtlichen Rahmenbedingungen in den letzten Jahren mehrfach angepasst. Dennoch bleibt die eingeschränkte Organverfügbarkeit die Hauptlimitation dieser Therapie, auch im Bereich der Herz- und Lungentransplantation. Beide Verfahren sind mittlerweile etablierte Therapieoptionen für selektierte Patienten mit terminalem Organversagen. Ziel ist die Verbesserung der Lebensqualität und des Überlebens. Der Erfolg der Therapie hängt maßgeblich von der Selektion geeigneter Empfänger sowie dem optimalen peri- und postoperativen Management ab, einschließlich einer lebenslangen spezialisierten Nachsorge. Die Komplexität der Therapie erfordert ein hohes Maß an speziellen Kenntnissen und Fertigkeiten. Der vorliegende Beitrag fasst den aktuellen Stand der Transplantationsmedizin thorakaler Organe mit dem Fokus auf den Inhalt der neuen Zusatzweiterbildung Transplantationsmedizin zusammen.

Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.

Heart transplantation across preformed donor‐specific HLA‐antibody barriers is associated with impaired short‐ and long‐term survival. Therefore, in recipients with preformed anti‐HLA antibodies, waiting for crossmatch‐negative donors is standard practice. As an alternative strategy, recipients with preformed anti‐HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor‐specific HLA‐antibodies to recipients without donor‐specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six‐month course of IgGAM. Among the 117 heart‐transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1‐year follow‐up, freedom from pulsed steroid therapy for presumed rejection and biopsy‐confirmed acute cellular or humoral rejection did not differ between groups. One‐year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch. A perioperative desensitization regimen leads to similar graft and patient survival rates for heart transplant recipients with preformed donor‐specific HLA antibodies, compared to those without pre‐formed donor‐specific antibodies.

Allogeneic lung transplantation (LuTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon reperfusion of the explanted, ischemic lung during implantation remains a crucial mediator of primary graft dysfunction (PGD) and early allo‐immune responses. Ex vivolung perfusion (EVLP) displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LuTx utilizing EVLP, while long‐term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation through reconditioning the injured lung and diminishing IRI through storing the explanted lung in a non‐ischemic, perfused, and ventilated status. In this work, we review potential mechanisms of EVLP that may attenuate IRI and improve organ quality. Moreover, we dissect experimental treatment approaches during EVLP that may further attenuate inflammatory events deriving from tissue ischemia, shear forces or allograft rejection associated with LuTx. This minireview examines the impact on ischemia reperfusion injury derived inflammation of ex vivo lung perfusion and other promising experimental approaches to improve donor lung quality.

Allogeneic lung transplantation (LuTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon reperfusion of the explanted, ischemic lung during implantation remains a crucial mediator of primary graft dysfunction (PGD) and early allo-immune responses. Ex vivolung perfusion (EVLP) displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LuTx utilizing EVLP, while long-term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation through reconditioning the injured lung and diminishing IRI through storing the explanted lung in a non-ischemic, perfused, and ventilated status.

Graphical Abstract

Ability to thrive and time-to-recurrence following treatment are important parameters to assess in patients with glioblastoma multiforme (GBM), given its dismal prognosis. Though there is an ongoing debate whether it can be considered an appropriate surrogate endpoint for overall survival in clinical trials, progression-free survival (PFS) is routinely used for clinical decision-making.

Heart retransplantation remains a controversial issue, due to the overall shortage of donor organs. Many patients put on the waiting list for retransplantation, decompensate rapidly, and do not survive. The use of veno-arterial extracorporeal life support remains an option in such emergency situations as bridge-to-recovery or bridge-to-transplantation therapy. In peripheral femoral configuration, veno-arterial extracorporeal life support improves the patient’s condition by relieving low-cardiac output but immobilizes him or her for an uncertain period of time. The upper-body cannulation is an alternative approach, which allows to maintain the patient awake and mobile. We present two cases of midterm circulatory support as a bridge to heart retransplantation, using upper-body cannulation veno-arterial extracorporeal life support. Two male patients, presenting with progressive cardiac decompensation due to severe graft rejection, were placed on upper-body veno-arterial extracorporeal life support. The stabilization of hemodynamics and improvement of end-organ perfusion could be achieved after extracorporeal life support initiation. After 48 and 40 days, respectively, on extracorporeal life support with active physical therapy and no major adverse events, both patients received a cardiac retransplantation and were eventually discharged home. The presented cases are the first reported where a successful cardiac retransplant was performed following prolonged upper-body extracorporeal life support.

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Graphical Abstract

The use of adjuvant radiotherapy is controversial in patients with atypical meningiomas treated with gross total resection (GTR). This study aimed to determine whether clinico-pathological features could be helpful to predict the recurrence risk in this group of patients and to identify high-risk ones who could benefit from adjuvant treatment. We collected 200 patients with primary atypical meningiomas treated with GTR but with no adjuvant radiotherapy from 5 different centers. A risk score, formulated by assigning 1 point for the presence and 0 points for the absence of 5 high-risk parameters (male sex, parasagittal site, Simpson grade 3, mitotic index ≥ 6/10 HPF, and sheeting), was the most significant predictor of recurrence. A score ≥2 was associated with 4.7 risk of shorter disease-free survival (p < 0.0001). Our findings indicate that the presence of at least 2 clinico-pathological high-risk factors predicts recurrence of totally resected primary atypical meningiomas and could be helpful for identifying patients who could benefit from adjuvant radiotherapy.

Real-time neuropsychological testing (RTNT) was used to test whether permanent endovascular occlusion of the insular branch of the left middle cerebral artery (MCA) helped avoid cognitive and neurological complications following the procedure. This patient suffered from a fusiform aneurysm along the insular branch of the MCA in the territory supplied in the left inferior frontal gyrus, around Broca's area. Pre-intervention neuropsychological testing was normal.

La desnutrición influye en la evolución clínica de los pacientes con insuficiencia cardiaca. El objetivo es analizar el impacto del estado nutricional preoperatorio evaluado mediante el índice de riesgo nutricional (IRN) en el pronóstico de los pacientes que recibieron dispositivos de asistencia ventricular izquierda de flujo continuo (DAVI-fc).

Introduction: Lymphangioleiomyomatosis (LAM) is a rare disease in women, leading to progressive deterioration of lung function and respiratory failure. We describe the outcome of patients with end-stage LAM who underwent lung transplantation at our center.Materials and Methods: The records of patients with LAM transplanted at our institution between February 1997 and May 2015 were reviewed retrospectively. Morbidity and mortality were analyzed, and actuarial survival was calculated using Kaplan-Meier methods. The cumulative survival of transplant patients with LAM at our center was compared with survival after transplantation due to different diseases at our center and the results of the International Society for Heart and Lung Transplantation. Quality of life was assessed by a patient self-report at the end of the first postoperative year.Results: During the study period, 25 patients underwent lung transplantation for LAM. All patients were women with a mean age of 50 (9) years. Thirteen patients (52%) had undergone previous thoracotomy. All patients (100%) received bilateral lung transplantation. One (4%) case of in-hospital mortality occurred and 9 (36%) late deaths. Two (8%) cases of late death were due to chronic lung allograft dysfunction. The 1-, 3-, and 5-year survival rates were 92%, 84%, and 76%, respectively. Quality-of-life ratings were above the normal in all eight 36-Item Short Form Health Survey subscales 1 year after transplantation.Conclusions: Lung transplantation offers a valuable therapy for patients with end-stage pulmonary LAM.

Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology.

This retrospective study presents our 4‐year experience of preemptive treatment of early anti‐HLAdonor specific antibodies with IgA‐ and IgM‐enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti‐CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4‐year follow‐up, respectively, graft survival (%) was 79 versus 81 (P= .59), freedom (%) from biopsy‐confirmed rejection 57 versus 53 (P= .34), and from chronic lung allograft dysfunction 82 versus 78 (P= .83). After lung transplantation, patients with early donor‐specific antibodies and treated with IgA‐ and IgM‐enriched immunoglobulins had 4‐year graft survival similar to patients without antibodies and showed high antibody clearance. Lung‐transplanted patients who develop early anti‐HLA donor‐specific antibodies and are treated with a protocol based on successive infusion of IgA‐ and IgM‐enriched intravenous immunoglobulins show good antibody clearance and graft survival, similar to the survival of patients without early donor‐specific antibodies.

This retrospective study presents our 4-year experience of preemptive treatment of early anti-HLA donor specific antibodies with IgA- and IgM-enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti-CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4-year follow-up, respectively, graft survival (%) was 79 versus 81 (P= .59), freedom (%) from biopsy-confirmed rejection 57 versus 53 (P= .34), and from chronic lung allograft dysfunction 82 versus 78 (P= .83). After lung transplantation, patients with early donor-specific antibodies and treated with IgA- and IgM-enriched immunoglobulins had 4-year graft survival similar to patients without antibodies and showed high antibody clearance.

Lung retransplantation is a demanding procedure with outcomes lagging primary transplantation and less invasive retransplantation of the lung via sternum-sparing anterolateral thoracotomies and off-pump is a safe procedure with low associated morbidity and favorable mid-term survival.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLADat 2 years. Among lung‐transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25highT cells and further analyzed for CTLA4, CD127, FoxP3, and IL‐2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLADwithin 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+and CD4+CD25highIL‐2+T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLADat 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLADdevelopment. Salman and colleagues explore the relationship between the frequencies of T regulatory cell subpopulations and the development of chronic lung allograft dysfunction after lung transplantation and demonstrate an association between higher CD4+CD25highCD127low, FoxP3+, and IL‐2+T cell frequencies early after lung transplantation and less chronic lung allograft dysfunction at two years.

Regulatory T cells (Treg) can regulate alloantigens and may counteract chronic lung allograft dysfunction (CLAD) in lung transplantation. We analyzed Treg in peripheral blood prospectively and correlated percentages of subpopulations with the incidence of CLAD at 2 years. Among lung-transplanted patients between January 2009 and July 2011, only patients with sufficient Treg measurements were included into the study. Tregs were measured immediately before lung transplantation, at 3 weeks and 3, 6, 12, and 24 months after transplantation and were defined as CD4+CD25highT cells and further analyzed for CTLA4, CD127, FoxP3, and IL-2 expressions. Between January 2009 and July 2011, 264 patients were transplanted at our institution. Among the 138 (52%) patients included into the study, 31 (22%) developed CLAD within 2 years after transplantation. As soon as 3 weeks after lung transplantation, a statistically significant positive association was detected between Treg frequencies and later absence of CLAD. At the multivariate analysis, increasing frequencies of CD4+CD25highCD127low, CD4+CD25highFoxP3+and CD4+CD25highIL-2+T cells at 3 weeks after lung transplantation emerged as protective factors against development of CLAD at 2 years. In conclusion, higher frequencies of specific Treg subpopulations early after lung transplantation are protective against CLAD development.