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Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty-three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 [IQR 49-64] years vs. 48 [32-59]; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day [1-3] vs 2 days [1-3]; p = .37, deaths 0% [0/33] vs. 2% [11/560], p = .99 respectively). Intermediate-term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end-stage lung disease.

Background As lung transplantation (LTX) is a valuable treatment procedure for end-stage pulmonary disease, delayed referral to a transplant center should be avoided. We aimed to conduct a single-center analysis of the survival time after listing for LTX and waitlist mortality in each disease category in a Japanese population. Methods We included patients listed for LTX at Tohoku University Hospital from January 2007 to December 2020 who were followed up until March 2021. Pulmonary disease was categorized into the Obstructive, Vascular, Suppurative, Fibrosis, and Allogeneic groups. Risk factors for waitlist mortality were assessed using a Cox proportional hazards model. The Kaplan–Meier method was used to model time to death. Results We included 269 LTX candidates. Of those, 100, 72, and 97 patients were transplanted, waiting, and dead, respectively. The median time to LTX and time to death were 796 days (interquartile range [IQR] 579–1056) and 323 days (IQR 129–528), respectively. The Fibrosis group showed the highest mortality (50.9%; p Conclusions In Japan, the waiting time is extremely long and candidates with Fibrosis have high mortality. There is a need to document outcomes based on the underlying disease for listed LTX candidates to help determine the optimal timing for listing patients based on the estimated local waiting time.

OBJECTIVES The objective of the present study was to examine the effect of venovenous (VV) extracorporeal membrane oxygenation (ECMO) use on the haemodynamics during single lung transplantation (SLT) and postoperative course. METHODS Forty-seven patients who underwent SLT for end-stage lung diseases in our lung transplant centre between January 2010 and December 2019 were included in this study. The recipients were divided into 3 groups according to the type of intraoperative ECMO. No type of ECMO was intra-operatively used in the patients of the no use of ECMO (NO ECMO) group. The patients in the venoarterial (VA) and VV ECMO groups were put on VA and VV ECMO during the surgery, respectively. The data were compared among the 3 groups. RESULTS There were 13 SLT cases in the NO ECMO group, 23 SLT cases in the VA ECMO group and 11 SLT cases in the VV ECMO group. Re-exploration for bleeding was performed in 3 (13.0%) recipients in the VA ECMO group. No recipients required re-exploration in the other groups. In the NO ECMO group, systolic pulmonary arterial pressure (PAP) was significantly elevated during the main pulmonary artery clamp on the SLT side and it was decreased in the VA ECMO group because of the bypass flow. Interestingly, systolic PAP was significantly decreased in the VV ECMO group as well. CONCLUSIONS VV ECMO decreases the PAP during SLT, which could be a choice for extracorporeal life support during lung transplant surgery for patients, even those with pulmonary hypertension.

To date, reports addressing the antibody response following mRNA SARS-CoV-2 vaccination in lung transplant (LTX) recipients are limited. Thus, the aim of this clinical study was to investigate the efficacy and safety of the vaccines in LTX recipients compared to controls.An open-label, nonrandomized prospective study was conducted at Tohoku University Hospital. LTX recipients and controls who received either the BNT162b2 vaccine or the mRNA-1273 vaccine were recruited, and SARS-CoV-2 IgG was measured before and after vaccination. The adverse events were reviewed. Predictors of negative serology after vaccination were evaluated with logistic regression.Forty-one LTX recipients and 24 controls were analyzed. Although all controls had a positive antibody response to a SARS-CoV-2 mRNA vaccine, antibody response was found in 24.4% of LTX recipients (p .0001). The amount of SARS-CoV-2 IgG following the 2nd dose significantly climbed to 6557 AU/mL in controls, whereas the increase in IgG in LTX recipients was 8.3 AU/mL (p .0001). Fewer LTX recipients developed systemic fever than controls (p .0001) despite equivalent overall adverse event percentages in both groups. A higher plasma concentration of mycophenolate was a significant predictor of negative serology (p = .032).An impaired antibody response to mRNA vaccines was significantly found in LTX recipients compared to controls and was associated with the plasma concentration of mycophenolate. While repeating mRNA vaccination may be one of the strategies to improve antibody response given the safety of the vaccines, emerging data on humoral immune responses based on immunosuppression regimens in LTX recipients should be studied (jRCT1021210009).

Background The use of a novel extracellular oxygen carrier (EOC) preservation additive known as HEMO2Life has recently been shown to lead to a superior preservation of different types of solid organs. Our study aimed to investigate the effect of this EOC on extending lung preservation time and its mechanism of action. Methods Donor pigs were randomly allocated to either of the following 2 groups (n = 6 per group): (1) 36 hours cold preservation or (2) 36 hours cold preservation with 1 g/liter of EOC. The lungs were evaluated through 12 hours of normothermic ex vivo lung perfusion (EVLP) followed by a left-single lung transplant into a recipient pig. Grafts were reperfused for 4 hours, followed by right pulmonary artery clamping to assess graft oxygenation function. Results During EVLP assessment, EOC-treated lungs showed improvements in physiologic parameters, whereas the control lungs deteriorated. After a total of 48 hours of preservation (36 hours cold + 12 hours normothermic EVLP), transplanted grafts in the treatment group displayed significantly better oxygenation than in the controls (PaO2/FiO2: 437 ± 36 mm Hg vs 343 ± 27 mm Hg, p = 0.041). In addition, the use of EOC led to significantly less edema formation (wet-to-dry ratio: 4.95 ± 0.29 vs 6.05 ± 0.33, p = 0.026), less apoptotic cell death (p = 0.041), improved tight junction preservation (p = 0.002), and lower levels of circulating IL-6 within recipient plasma (p = 0.004) compared with non-use of EOC in the control group after transplantation. Conclusion The use of an EOC during an extended pulmonary preservation period led to significantly superior early post-transplant lung function.

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life-sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.

The patient was a 41-year-old man. He was diagnosed with pleurisy and came to our hospital. The pleural effusion and pleurisy remained even after administration of sufficient doses of antibiotics. A thorough examination revealed an anterior mediastinal tumor. Six months later, pericarditis also developed. Autoimmune diseases, infections, and malignant diseases were suspected, but a definitive diagnosis could not be made. In order to confirm the diagnosis, anterior mediastinal tumor resection and pleural biopsy were performed. The anterior mediastinal tumor was diagnosed as cholesterin granuloma pathollogically. Cholesterin granuloma is a granuloma formed by deposition of cholesterin crystals and cholesterin granuloma occurring in the mediastinum is extremely rare.

BackgroundWhile lung transplant (LTX) can be an effective therapy to provide the survival benefit in selected populations, post-transplant outcome in LTX recipients with bronchiectasis other than cystic fibrosis (CF) has been less studied.Pseudomonas aeruginosa, often associated with exacerbations in bronchiectasis, is the most common micro-organism isolated from LTX recipients. We aimed to see the outcomes of patients with bronchiectasis other than CF after LTX and seek the risk factors associated with pre- and post-transplantPseudomonasstatus.MethodsPatients who underwent LTX at Tohoku University Hospital between January 2000 and December 2020 were consecutively included into the retrospective cohort study. Pre- and post-transplant prevalence ofPseudomonascolonization between bronchiectasis and other diseases was reviewed. Post-transplant outcomes (mortality and the development of chronic lung allograft dysfunction (CLAD)) were assessed using a Cox proportional hazards and time-to-event outcomes were estimated using the Kaplan–Meier method.ResultsLTX recipients with bronchiectasis experienced a high rate of pre- and post-transplantPseudomonascolonization compared to other diseases with statistical significance (p p p = 0.522), and the bronchiectasis was not a trigger for death (HR 1.62, 95% CI 0.63–4.19). On the other hand, the chance of CLAD onset in bronchiectasis was comparable to non-bronchiectasis (Log-rankp = 0.221), and bronchiectasis was not a predictor of the development of CLAD (HR 1.88, 95% CI 0.65–5.40).ConclusionsDespite high prevalence of pre- and post-transplantPseudomonascolonization, the outcome in LTX recipients with bronchiectasis other than CF was comparable to those without bronchiectasis.

Background and Objectives To treat organ transplant patients with mycobacterial infection, physicians need to pay attention to interaction between drugs used against mycobacteria and immunosuppressants. The purpose of this report is to describe the clinical features of and treatment for mycobacterial infection in lung transplant (LTx) recipients. Methods To investigate the incidence, treatment, and outcome for mycobacterial infection, we retrospectively reviewed 100 LTx recipients in our program since 2000. Results Four recipients (4.0%) developed mycobacterial infection. Three recipients took tacrolimus, and 1 received cyclosporine with mycophenolate mofetil and a steroid for immunosuppression. Tuberculosis (TB) was isolated from 2 recipients, and non-tuberculous mycobacteriosis (NTM) was detected in the other 2. We treated the patients with levofloxacin + isoniazid + pyrazinamide + ethambutol (EB) for TB and clarithromycin (CLM) + EB for NTM to avoid interaction of calcineurin inhibitors (CNI: 8-10 ng/mL in trough level) with rifampicin (RFP). In treating the patients with NTM, we were able to maintain an adequate blood concentration of CNI by decreasing the dosage from one-half to one-quarter. All mycobacterial infections were controlled with treatment. In 1 patient with chronic obstructive pulmonary disease (COPD) infected with TB in the native lung, the forced expiratory volume in 1 second (FEV1) unexpectedly increased from 1890 mL before infection to 2320 mL possibly due to organization of the native lung. Conclusions We were able to manage the mycobacterial infections using drugs other than RFP without any cases of acute rejection under adequate immunosuppression. Organization of the native lung with TB infection unexpectedly resulted in improvement of FEV1 in a COPD patient.

Background The median sternotomy approach in sleeve pneumonectomy enables diseased lung ventilation in selected cases, which may reduce the difficulty in achieving anastomosis under intubation of the left main bronchus. However, with median sternotomy, the ascending aorta requires repeated mobilization to expose the operative field for anastomosis, which can cause an aortogenic embolic stroke. Case presentation A 70-year-old Asian man presenting 6 months after developing hemoptysis was diagnosed with right upper lobe lung cancer (stage T4N0M0), invading the lower trachea and basal bronchus. Preoperative computed tomography revealed ascending aorta calcification. Right sleeve pneumonectomy was performed using median sternotomy with diseased lung ventilation. The ascending aorta was repeatedly mobilized to adequately expose the tracheobronchial bifurcation. Surgery was uneventful, but he did not recover complete consciousness even after termination of anesthesia. Mild paralysis of both upper extremities was observed. Head magnetic resonance imaging on postoperative day 1 revealed multiple small acute infarctions in the brain, possibly caused by mobilization of the aorta. He received anticoagulation therapy and rehabilitation and was discharged on postoperative day 30. Conclusion The median sternotomy approach in sleeve pneumonectomy enables diseased lung ventilation. However, the possibility of aortogenic embolic stroke should be considered when calcification of the ascending aorta is observed on preoperative computed tomography.

Purpose Left ventricular assist devices (LVADs) have emerged as an important treatment option for bridging patients with heart failure to transplant. LVADs have shown improved survival; however, the impact of LVAD type on the quality of life (QoL) while on long-term LVAD support is unknown. We aimed to evaluate the QoL of patients while supported with a LVAD in Japan. Methods 299 patients enrolled in the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS), who were listed for transplant or likely to be listed, received a LVAD from 2010 to 2018 and had full QoL data, were enrolled. QoL data, such as visual analogue scale (VAS) and EQ-5D-3L by 5 dimensions (5D: mobility, self-care, usual activities, pain/discomfort and anxiety/depression) before and at 3- and 12-months after implantation of a LVAD were obtained from the J-MACS Registry. These patients were divided into 3 groups; primary implantable LVAD (iLVAD) (N=263), primary paracorporeal LVAD (pLVAD) (N=9) and bridge from paracorporeal to implantable LVAD (BTB) (N=27). Results VAS in all groups significantly increased from before to 3- and 12-months after LVAD implantation(p Conclusion QoL as VAS and 5D were significantly improved after implantation of any LVAD type. However, VAS and 5D except anxiety/depression in patients with pLVAD were significantly lower and more problems than those in patients with iLVAD. These differences were eliminated by converting from pLVAD to iLVAD. BTB might be a beneficial treatment option to improve QoL as well as patient's survival.

Purpose Left ventricular assist device (LVAD) has been reported to improve pulmonary hypertension (PH) due to left heart disease (PH-LHD). However, prevalence of combined post- and pre-capillary PH (Cpc-PH) in patients with PH-LHD and the impact of LVAD implantation on Cpc-PH has not been fully elucidated. This study aimed to investigate hemodynamic changes following LVAD implantation in patients with PH-LHD to assess pulmonary vascular reverse remodeling. Methods Eighty-nine patients with advanced heart failure complicated by PH-LHD undergoing LVAD implantation who received serial right heart catheterizations at least 3 time points (before, early after, and 1-year after implantation) were retrospectively reviewed. Patients were divided into 2 groups as Cpc-PH group (n=50): pulmonary vascular resistance (PVR) > 3 Wood unit (WU) or diastolic pulmonary pressure gradient (DPG) ≥ 7 mmHg, and isolated post-capillary PH (Ipc-PH) group (n=39). Results Values of brain natriuretic peptide and transaminase in Cpc-PH group were higher than those in Ipc-PH group. Cpc-PH patients were consisted of 41 with PVR > 3 WU, 8 with PVR > 3 WU and DPG ≥ 7 mmHg, and 1 with DPG ≥ 7 mmHg preoperatively. Median values of PVR in both groups significantly decreased early after LVAD implantation [from 4.1 to 2.7 WU (p 3 WU (n=14) or DPG ≥ 7 mmHg (n=1) at that point. Among these 15 patients, 4 patients still remained on their PVR > 3 WU (n=3) or DPG ≥ 7 mmHg (n=1) even 1-year after LVAD implantation. PVR and DPG in these 4 patients turned to normal values at 3-year after implantation. Conclusion Over half of patients with PH-LHD were complicated by Cpc-PH in our study cohort. LVAD implantation readily improved hemodynamics regardless of complication of Cpc-PH, whereas 15 patients were still found to be PVR > 3 WU or DPG ≥ 7 mmHg which should be considered as persistent Cpc-PH. We speculate that most of Cpc-PH in patients with PH-LHD might be caused by alteration of vascular tone which will be promptly relieved by substantial left ventricular unload, however a certain number of patients with Cpc-PH might develop structural remodeling of pulmonary vasculature which requires months or years to achieve pulmonary vascular reverse remodeling.

Purpose Endomyocardial biopsy (EMB) is a gold standard to detect acute cellar cardiac rejection (ACR), but due to its invasiveness, a new non-invasive approach is warranted. Our final goal is to identify new biomarkers corresponding to ACR severity. Using RNA-seq analysis, we found specific gene expression profiles in EMB specimens corresponding to the grades of ISHLT criteria. We also established a transcriptome analysis method utilizing an FFPE (formalin fixed paraffin embedded) EMB section remained after pathological examination. Methods 1. Gene expression profiling in fresh frozen EMB section: 7 cardiac recipients who had pathological ACR were enrolled. They were divided into two groups: patients with before and at rejection ISHLT grade 1A (G-going; N=3) and with at and after treating rejection grade 1A (G-resolving; N=4). Transcriptome analysis was performed using a fresh frozen section (0.5 - 3 mm wide, 7 µm thickness). 2. Establishment of a 3’mRNA-seq method utilizing thin FFPE EMB section: 28 myocardial specimens (grade 0 in 7, 1A in 12, 2 in 2, 3A in 4 and quilty in 3) were analyzed. 3’mRNA-seq libraries were prepared using total RNA isolated from an FFPE section (1-2 mm wide, 5 µm) remained after pathological examination. 3. GSEA (Gene Set Enrichment Analysis) and DGE analysis: After RNA-sequencing, gene expression profiling was analyzed by GSEA and clustered by k-means. Results In G-going, we identified up-regulation of the genes mainly related to ACR, interferon gamma, inflammation, and ILG-JAK-STAT3 signaling, while in G-resolving, we identified down-regulation of these genes. Inflammatory responses were also observed in 3’mRNA-seq analysis using FFPE section. We also separated 270 up-regulating genes in grade3A and 229 ACR related genes associated with ISHLT criteria. In our analysis, most of these identified genes were not listed in AlloMap ®. Conclusion Although these analyses were preliminary because of the 1st analysis stage, these technique for analyzing gene expressions using a tiny myocardial sample may have a role to find new biomarkers associated with ACR.

Purpose An extracorporeal centrifugal-flow left ventricular assist device (CF-E-LVAD) system (BR16010) was newly developed. Since implantation of the durable implantable LVAD (I-LVAD) is still controversial in patients with cardiogenic shock or refractory heart failure because of its significant inferiority of outcomes as compared with higher INTERMACS profile patients, short-term E-LVADs have been still clinically important for bridging strategy for the next definitive treatment. Our aim of this study was to evaluate the influence of the novel developed CF-E-LVAD on the clinical prognosis in patients with bridging strategy, as compared with conventional extracorporeal pulsatile flow LVAD (PF-E-LVAD). Methods We retrospectively reviewed the medical records of 62 patients who were implanted E-LVAD as bridging strategy from April 2011 to January 2019. Six patients (9.7%) were implanted CF-E-LVAD. The clinical prognosis until 30 days after E-LVAD implantation, and the change of cardiac function and laboratory data at the early follow up were evaluated. Results Improvement of left ventricular ejection fraction was significantly greater in the CF-E-LVAD group than in the PF-E-LVAD group (217.9 [147.8 to 335.3] vs 38.3 [-21.7 to 128.8] %, P=0.010). Serum total bilirubin level significantly improved in CF-E-LVAD group than in the PF-E-LVAD group (-7.9 [-33.3 to 82.4] vs 68.8 [10.0 to 202.1] %, P=0.041). Although clinical courses, including death, cerebrovascular accidents and re-thoracotomy due to removal of mediastinal hematoma, were no significant difference between two groups, almost half (54.5%) in the PF-E-LVAD group was still ongoing the E-LVAD support at the 30 days post-E-LVAD implantation while only one patient (16.7%) was supported with E-LVAD in the CF-E-LVAD group. Conclusion The novel developed CF-E-LVAD system might influence on the earlier recovery of cardiac function and the multiple organ failure, and lead to the earlier decision for next definitive strategy.

Purpose Giant pulmonary arterial aneurysm (PAA) is a rare but serious complication for patients with pulmonary hypertension (PH). Heart-lung transplantation or lung transplantation with a full length of donor pulmonary artery (PA) for pulmonary artery reconstruction (PAR) are options for PH complicated with a giant PAA involving PA trunk to main PAs. We have been using donor aorta for the reconstruction of PA for these lung transplant cases. This study aimed to describe our intermediate-term outcomes of lung transplantation with PAR using donor aorta for PH complicated with a giant PAA. Methods This is a single center retrospective review from March 2000 to May 2020. We reviewed cadaveric lung transplantations for PH and compared the outcomes of lung transplantation with PAR (PAR group) with those without PAR (non-PAR group). Results Twenty-five PH patients underwent cadaveric lung transplantation. Among them, 5 patients with a giant PAA underwent lung transplantation with PAR using donor aorta. Representative 3D-CT images of a giant PAA and the reconstructed PA are shown in Figure A. The diameter of the PA trunk was significantly larger in the PAR group compared to the non-PAR group (Figure B). As expected, operative time was significantly longer in the PAR group compared to the non-PAR group (PAR, 1204 minutes; non-PAR, 965 minutes, p=0.035). On the other hand, primary graft dysfunction grade, 30-day mortality (PAR, 0%; non-PAR, 5.0%), 5-year survival rate (PAR, 100%; non-PAR, 73.9%, Figure C), and 6 minutes walk distance at 1 year after lung transplantation (PAR, 522 m; non-PAR, 526m) were not significantly different between the groups. The donor aortas used for PAR did not show constriction, obstruction, enlargement, or infection during the observation period. Conclusion Our experience supports that lung transplantation with PAR using donor aorta is a feasible surgical option for PH complicated with a giant PAA.

Purpose Heparin-induced thrombocytopenia (HIT) is an immune-mediated condition associated with thrombocytopenia and thrombotic complications. The condition is increasingly recognized in hospitalized patients including severely injured trauma patients. Because these patients may eventually be considered for organ donation, management of the HIT screen positive donor has become an important issue in transplant surgery. We describe the recent management of 2 cardiac allograft donors with HIT. Methods At organ recovery, both male adult donors were hemodynamically stable with a normal appearing heart and no evidence of thrombosis. The donor underwent a routine multiple organ allograft recovery with argatroban infused over 15 minutes immediately before aortic cross-clamping after confirming activated clotting time (ACT) of greater than 400 sec. The cardiac allograft was flushed in the donor operating room with a total of 4 liters of cold Celsior solution. These hearts were transplanted in patients with dilated cardiomyopathy and cardiac sarcoidosis by modified bicaval anastomosis technique using heparin for anticoagulation therapy during cardiopulmonary support. Both were bridged with implantable left ventricular assist device (Heart Mate II and Jarvik 2000, respectively). Results This management strategy resulted in successful multiple organ transplants (Case 1: heart, two single lungs, liver, 2 kidney, case 2: heart, bilateral lung, liver, pancreas, 2 kidneys). Neither of the heart and other recipients demonstrated signs or symptoms of HIT, or neither had any postoperative thrombotic complications.. Conclusion Based on this experience, a treatment algorithm for managing HIT donors using argatroban is proposed for heart donors as well as other organ donors

Background The therapeutic drug monitoring of mycophenolic acid (MPA) has been investigated for renal and heart transplantations; however, its usefulness in lung transplantation is unclear. Methods The MPA area under the plasma concentration-time curve (AUC) was calculated in 59 adult lung transplant recipients. The MPA AUC0-12 s were compared among the three groups determined by the presence of adverse events (no events, infection, and chronic lung allograft dysfunction [CLAD]). Next, MPA AUC0-12 thresholds for the adverse events were identified by receiver operating characteristic analysis. Cumulative occurrence rate of the adverse events was compared between two groups (adequate and inadequate groups) according to the thresholds. Results The MPA AUC0-12 s in the no event, infection, and CLAD groups were 30.3 ± 6.5, 36.8 ± 10.7, and 20.6 ± 9.6 µg·h/mL, respectively (P = .0027), while the tacrolimus trough levels were similarly controlled in the groups. The thresholds of MPA AUC0-12 for the occurrence of infection and CLAD were 40.5 and 22.8 µg·h/mL, respectively. The cumulative occurrence rate of adverse events of adequate group (15.3%) was significantly lower than that of inadequate group (56.0%) (P = .0050). Conclusions The MPA AUC0-12 may affect the occurrence of adverse events in lung transplant recipients.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

The purpose of this study was to assess the usefulness of positron emission tomography/computed tomography (PET/CT) in the differential diagnosis of anterior mediastinal tumors. A total of 94 patients with anterior mediastinal masses or nodules (male, n = 41; female, n = 53; age, 17–84 years) were retrospectively evaluated. All patients were evaluated by PET/CT and the masses or nodules were histologically diagnosed in our institution. Anterior mediastinal masses and nodules were classified into two disease categories: Low (thymic hyperplasia, thymoma, mature teratoma, and MALT lymphoma) and High (thymic carcinoid, thymic cancer, diffuse large B-cell lymphoma, T-cell lymphoblastic lymphoma, Hodgkin’s lymphoma, and malignant germ cell tumors) groups. The sensitivity and specificity of maximum standardized uptake value (SUVmax) 7.5 for the detection of High group were 77% and 100%, respectively. The SUVmax distributions of the WHO histological thymoma types and Masaoka stage thymomas extensively overlapped. Masaoka stage III thymomas had significantly higher SUVmax than Masaoka stage I thymomas. Regarding the TNM classification, the SUVmax of T3 and T1b thymomas was higher than T1a thymoma. Although the SUVmax of each disease overlapped, PET/CT findings provided useful information for the differential diagnosis of anterior mediastinal masses.

Objectives Ex vivo lung perfusion provides an innovative method to assess and repair donor lungs. The current Toronto ex vivo lung perfusion protocol can reliably and reproducibly preserve lungs for 12 hours. A longer ex vivo lung perfusion preservation time could enable the application of more advanced repair therapies and the rescue of more donor lungs for lung transplant. Our objective was to achieve stable 24-hour normothermic ex vivo lung perfusion. Methods We systematically examined 3 modifications of ex vivo lung perfusion perfusate administration in a large animal 24-hour ex vivo lung perfusion model. Pig lungs were assigned to 4 groups (n = 5 per group): (1) control; (2) continuous replacement of ex vivo lung perfusion perfusate; (3) modified feed, which used a modified solution to maintain perfusate osmolality by adjusting glucose and sodium levels; and (4) total parenteral nutrition, in which we added parenteral nutrition to the perfusate. Results Only 1 lung in the control group completed 24-hour ex vivo lung perfusion. However, 24-hour perfusion was achieved in 4 lungs in the continuous replacement group, 3 lungs in the modified feed group, and 4 lungs in the total parenteral nutrition group. The total parenteral nutrition group achieved significantly longer stable perfusion time compared with control (P = .03). Lung function was significantly improved and inflammatory cytokine production was reduced in the continuous replacement and total parenteral nutrition groups compared with control. Conclusions Modifications of ex vivo lung perfusion perfusate toward achieving a stable homeostatic state can extend perfusion time for up to 24 hours. Although these modifications allow for prolonged ex vivo lung perfusion, further research will be required to develop stable lung support beyond 24 hours.

Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.

We report a very rare case of pulmonary chromomycosis caused by Scedosporium prolificans that developed after lung transplantation and was successfully treated with endobronchial topical amphotericin B instillation. The subject was a woman in her 50s with a history of bilateral lobar lung transplantation from living donors for idiopathic pulmonary hypertension. Eight years after the lung transplantation, chest radiography X-ray and computed tomography showed an abnormal shadow in the right lung. Bronchoscopic findings showed obstruction by a fungal component at the laterobasal bronchus B9. She was diagnosed with pulmonary chromomycosis after S. prolificans was detected in the bronchial aspirate. Systemic antifungal treatment with itraconazole was ineffective. Therefore, we administered topical amphotericin B weekly via endobronchial instillation and replaced oral itraconazole with voriconazole. The endobronchial procedure was safe and tolerable. Bronchial obstruction improved after three 3 instillations. We continued topical amphotericin B instillation once every 3 months for 2 years, and the abnormal shadow nearly disappeared. This case report describes infection by S. prolificans, which rarely becomes an etiologic agent in lung transplant patients, and shows that endobronchial topical amphotericin B instillation is a therapeutic option when systemic antifungal treatment is ineffective.

Using a rat model of allograft lung transplantation, we investigated the effectiveness of mesenchymal stromal cells (MSCs) as prophylactic and therapeutic agents against the acute rejection of lung grafts. Lung grafts were harvested from donor rats and transplanted orthotopically into major histocompatibility complex-mismatched rats. MSCs were administered to the recipients once (on day 0) or twice (on days 0 and 3) after transplantation. The grade of acute rejection was evaluated both macroscopically and microscopically 6 days after transplantation. To elucidate the related mechanism, mRNA levels of inflammatory cytokines and immunomodulatory receptors in the transplanted grafts were measured using quantitative RT-PCR. The lung graft tissue from the rats that received MSCs post-surgically was protected from acute rejection significantly better than that from the untreated controls. Notably, the rats administered MSCs twice after surgery exhibited the least signs of rejection, with a markedly upregulated mRNA level of PD-L1 and a downregulated mRNA level of IL-17A. This study assessed MSC protection of lung allografts from acute rejection by modulating T cell activity via enforced expression of PD-L1 in transplants and downregulation of IL-17A.

IL-17A is implicated in the pathogenesis of chronic lung allograft dysfunction, which limits survival after lung transplantation. While many cells express the IL-17 receptor A (IL-17RA) which is the main receptor for IL-17A, the cellular targets of IL-17A in development of post-transplant fibrosis are unknown. The purpose of this study was to determine whether IL-17RA expression by donor or recipient structural or bone marrow (BM) cells is required for the development of allograft fibrosis in a mouse intrapulmonary tracheal transplantation (IPTT) model. BM chimeras were generated using C57BL/6 and IL-17RA-knockout mice. After engraftment, allogeneic IPTTs were performed using the chimeric and BALB/c mice as donors or recipients. This allowed us to assess the effect of IL-17RA deficiency in recipient BM, recipient structural, donor BM, or donor structural compartments separately. Tracheal grafts, the surrounding lung, and mediastinal lymph nodes were assessed 28 days after IPTT. Only recipient BM IL-17RA deficiency resulted in attenuation of tracheal graft obliteration. In the setting of recipient BM IL-17RA deficiency, T cells and neutrophils were decreased in mediastinal lymph nodes. Additionally, recipient BM IL-17RA deficiency was associated with increased B220+PNAd+ lymphoid aggregates, consistent with tertiary lymphoid organs, in proximity to the tracheal allograft. In this IPTT model, recipient BM-derived cells appear to be the primary targets of IL-17RA signaling during fibrotic obliteration of the tracheal allograft.

Calcineurin inhibitors are a commonly used immunosuppressive drug and over 80% of lung transplant (LTx) recipients use tacrolimus. Sustained-release tacrolimus (SRT) was developed as a once-daily formulation, resulting in slower release and reduction in peak concentration compared with twice-daily immediate-release tacrolimus (IRT). Previous reports indicate that SRT may carry fewer side effects than IRT; however, the impact of SRT in bronchiolitis obliterans syndrome (BOS) after LTx is unclear.Our study objective was to evaluate the effect of SRT in BOS after LTx.We investigated the effect of SRT for BOS among 75 LTx recipients who were alive in 2017 in our LTx program. All analyses were carried out using student t test or F test.Thirty-five recipients took IRT, 32 recipients used SRT, 7 recipients used cyclosporine, and 1 patient who received bone marrow and a lung graft from the same donor did not use a calcineurin inhibitor. The most frequent reason for conversion of IRT to SRT was kidney dysfunction, followed by other IRT complications. Five recipients underwent conversion of IRT to SRT because of decline of forced expiratory volume in 1 second (FEV1) with fluctuation of the tacrolimus trough level. After induction of SRT, the fluctuation of the tacrolimus trough level was significantly reduced in 4 of 5 patients (P .05). Before drug form conversion, the FEV1 in these 5 patients was significantly decreased; however, this exacerbation of FEV1 was attenuated after SRT induction (P .05).SRT appeared to stabilize decline of FEV1 in patients with BOS possibly due to reducing the fluctuation of tacrolimus trough blood concentration.

Purpose Mouse orthotopic single lung transplantation (LTx) is a useful scientific model to explore LTx immunology. C57BL/10 (B10, H-2b) to C57BL/6 (B6, H-2b) minor alloantigen-mismatched LTx exhibits mild acute rejection and sometimes chronic fibrosis, mimicking human LTx where alloimmunity is dampened by immunosuppressants. We have observed variations in allograft histology across experiments, which were not explained by animal vendor or experimental conditions. The purpose of this study was to evaluate those variations objectively. Methods We performed a retrospective review of B10 to B6 LTx performed in our lab and sacrificed 28 days after LTx. LTx with an experimental intervention (e.g., usage of immunomodulatory agents or knock-out mice) were excluded. Surgeons 1 and 2 had had previous rodent LTx experience whereas Surgeons 3-5 had not. Each surgeon's first 10, middle 10, and last 10 LTx in our lab were pathologically graded in a blinded manner. Nonparametric Spearman correlation was computed to compare chronological variation across surgeons. Inter-surgeon differences were compared using two-way ANOVA. Results Data from 143 LTx were available from five surgeons’ records. Surgeon 1’s and 2’s pathology scores were mostly stable throughout the period (e.g. for B-grade rejection, Surgeon 1 r=0.10 and p=0.60, Surgeon 2 r=-0.11 and p=0.55), whereas those of surgeons 3-5 changed over time (e.g. for B-grade rejection, Surgeon 4 r=-0.57 and p Conclusion Mouse single LTx is a powerful model to study the underlying mechanisms of LTx biology. However, the surgeon- and experience-dependent variability in histopathological findings need to be taken into account when designing experimental protocols, particularly when the model has recently been acquired by the surgeon.

Purpose Previous work has shown that B cells are necessary for the development of chronic allograft fibrosis after ischemia-reperfusion injury (IRI) in a C57BL/10 (B10, H-2b)-to-C57BL/6 (B6, H-2b) minor alloantigen-mismatched mouse orthotopic lung transplant model. It remains unknown whether donor-derived B cells play a specific role in this phenomenon and how long they survive in the recipient. We hypothesized that donor B cells are short-lived and thus play a minimal role in the recipient. Methods We conducted B10 to B6 lung transplants without IRI using congenic donors and recipients. Donors were treated 2 days before transplantation with an anti-CD20 antibody or its isotype control. We used flow cytometry to track B cell populations in the donor and recipient before and up to 28 days after transplantation. Results Anti-CD20 effectively eliminated g85% of B cells from donor lungs prior to transplantation (Fig 1A). We observed low frequencies of donor (CD45.2+) B cells in the recipient (CD45.1+) peripheral blood after transplantation (Fig 1B). Despite profound B cell depletion in donor lungs, donor-derived B cells were unexpectedly still present in the allograft (median 3.5%, range 2.3-10%), thoracic lymph nodes (median 0.5%, range 0.2-1.5%) and spleen (median 1.2%, range 0.7-1.7%) at day 28 irrespective of anti-CD20 treatment (Fig 1C). B and plasma cells constituted g80% of donor-derived leukocytes observed in the recipient spleen at day 28. As expected, given the lack of IRI, allograft histology showed minimal rejection and fibrosis with no effect of anti-CD20 observed (Fig 1D). Conclusion Donor-derived B cells repopulated in the recipients to a similar extent in both groups on day 28. These findings suggest donor-derived B cells may play important functional roles after transplantation. An examination of the role of donor- and recipient-derived B cells in IRI-augmented lung allograft fibrosis is now underway.

Purpose Mouse orthotopic single lung transplantation (LTx) is a vital scientific model to explore lung transplantation (LTx) immunology. Minor alloantigen-mismatched LTx using C57BL/10 (B10, H-2b) to C57BL/6 (B6, H-2b) has mild acute rejection and sometimes chronic fibrosis, mimicking human LTx where alloimmunity is dampened by immunosuppressants. We have observed variations in allograft histology depending on individual microsurgeons’ experience. The purpose of this study was to compare pathological variations between individual surgeons and over time. Methods We performed a retrospective review of B10 to B6 LTx performed in our lab and sacrificed 28 days after LTx. LTx with an experimental intervention (e.g., usage of immunomodulatory agents or knock-out mice) were excluded. All pathological grading was performed in a blinded manner using HE B grade, Pl0.0001; % parenchymal fibrosis, P=0.1164; peri-airway fibrosis, Pl0.0001; obliterative airway fibrosis, Pl0.0001). Intra-surgeon chronological changes in pathological scores were statistically significant for A grade, B grade, and % parenchymal fibrosis (P=0.0024, P=0.0416, P=0.0097, respectively). Conclusion Mouse single lung transplantation is one of the most technically challenging animal models. It remains a powerful model to study underlying mechanisms of LTx biology. However, the significant learning curve and surgeon-dependent variability in histopathological findings need to be taken into account when designing experimental protocols.

Chronic lung allograft dysfunction (CLAD) limits long-term survival after lung transplant (LT). Ischemia-reperfusion injury (IRI) promotes chronic rejection (CR) and CLAD, but the underlying mechanisms are not well understood. To examine mechanisms linking IRI to CR, a mouse orthotopic LT model using a minor alloantigen strain mismatch (C57BL/10 [B10, H-2b ] → C57BL/6 [B6, H-2b ]) and isograft controls (B6→B6) was used with antecedent minimal or prolonged graft storage. The latter resulted in IRI with subsequent airway and parenchymal fibrosis in prolonged storage allografts but not isografts. This pattern of CR after IRI was associated with the formation of B cell-rich tertiary lymphoid organs within the grafts and circulating autoantibodies. These processes were attenuated by B cell depletion, despite preservation of allograft T cell content. Our observations suggest that IRI may promote B cell recruitment that drives CR after LT. These observations have implications for the mechanisms leading to CLAD after LT.

Ischemia-reperfusion injury (IRI) is one of the main causes of primary graft dysfunction that accounts for 25% of mortality after lung transplantation. Disruption of blood supply and subsequent reperfusion result in organ damage with activating innate and adaptive immune response, leading to inflammatory insults. The IRI after lung transplantation is primarily manifested by permeability pulmonary edema on the basis of pulmonary vascular endothelial cell injury as seen in acute respiratory distress syndrome (ARDS). Stem cells have potent anti-inflammatory and immunomodulatory properties through local paracrine mechanisms. The application of mesenchymal stem cells (MSCs) for ARDS as well as IRI in various organs, therefore, has been interested and extensively investigated in animal models with promising results. Furthermore, two recent clinical randomized, placebo-controlled pilot studies demonstrated that treatment of ARDS with MSCs appears to be safe and feasible.Muse cells are stress-tolerant and non-tumorigenic endogenous pluripotent-like stem cells. They comprise small proportions of cultured fibroblasts and MSCs and can be isolated from these populations. Muse cells are known to migrate to the damaged tissue after local or systemic administration, spontaneously differentiate into the tissue-compatible cells, and also secrete factors related to immunomodulation and tissue repair. We have recently shown the effect of Muse cells on ameliorating lung IRI in a rat model. With 2 h of warm ischemia and subsequent reperfusion on the left lung, the lung showed severe pulmonary edema. Administration of Muse cell through the left pulmonary artery immediately after reperfusion more significantly improved lung oxygenation capacity, compliance, and histological damage on days 1 and 3 after reperfusion compared with MSCs, and this was associated with higher expression levels of proteins related with anti-inflammation and tissue repair in the lung. Encouraging results of this study advocate further investigation of the ability of Muse cells to prevent and treat IRI after lung transplantation.

Purpose We developed an ex vivo lung CT (EVL-CT) technique that allows us to obtain detailed CT images and morphologically assess the retrieved lung from a donor for transplantation. After we recovered the lung graft from a brain-dead donor, we transported it to our hospital and CT images were obtained ex vivo before lung transplant surgery. The objective of this study was to investigate the correlation between the EVL-CT findings and post-transplant outcome in patients who underwent bilateral lung transplantation (BLT) or single lung transplantation (SLT). Methods We retrospectively reviewed the records of 70 patients with available EVL-CT data who underwent BLT (34 cases) or SLT (36 cases) in our hospital between October 2007 and September 2017. The recipients were divided into 2 groups (control group, infiltration group) according to the findings of EVL-CT of the lung graft in BLT and SLT, respectively. Recipients in the control group were transplanted lung grafts without any infiltrates (BLT control group, SLT control group). Recipients in the infiltration group received lung grafts with infiltrates (BLT infiltration group, SLT infiltration group). Results The recipients in the BLT infiltration group showed significantly slower recovery from primary graft dysfunction and a longer mechanical ventilation period and ICU stay period than those in the BLT control group. The mechanical ventilation period was significantly longer in the recipients in the SLT infiltration group than those in the SLT control group. Conclusion EVL-CT may predict the outcome of the early phase after lung transplantation.

In the original publication, Fig. 3 has been incorrectly published. The correct version of Fig. 3 is given in this Correction.

Ischemia-reperfusion injury (IRI) is one of the main causes of primary graft dysfunction that accounts for 25% of mortality after lung transplantation. Disruption of blood supply and subsequent reperfusion result in organ damage with activating innate and adaptive immune response, leading to inflammatory insults. The IRI after lung transplantation is primarily manifested by permeability pulmonary edema on the basis of pulmonary vascular endothelial cell injury as seen in acute respiratory distress syndrome (ARDS). Stem cells have potent anti-inflammatory and immunomodulatory properties through local paracrine mechanisms. The application of mesenchymal stem cells (MSCs) for ARDS as well as IRI in various organs, therefore, has been interested and extensively investigated in animal models with promising results. Furthermore, two recent clinical randomized, placebo-controlled pilot studies demonstrated that treatment of ARDS with MSCs appears to be safe and feasible.Muse cells are stress-tolerant and non-tumorigenic endogenous pluripotent-like stem cells. They comprise small proportions of cultured fibroblasts and MSCs and can be isolated from these populations. Muse cells are known to migrate to the damaged tissue after local or systemic administration, spontaneously differentiate into the tissue-compatible cells, and also secrete factors related to immunomodulation and tissue repair. We have recently shown the effect of Muse cells on ameliorating lung IRI in a rat model. With 2 h of warm ischemia and subsequent reperfusion on the left lung, the lung showed severe pulmonary edema. Administration of Muse cell through the left pulmonary artery immediately after reperfusion more significantly improved lung oxygenation capacity, compliance, and histological damage on days 1 and 3 after reperfusion compared with MSCs, and this was associated with higher expression levels of proteins related with anti-inflammation and tissue repair in the lung. Encouraging results of this study advocate further investigation of the ability of Muse cells to prevent and treat IRI after lung transplantation.