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Background Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that occurs in premature infants and the prognosis is variable depending on the comorbidities including fibrosis, emphysema, or pulmonary hypertension (PH). We present a case of a 9-year-old girl who developed PH associated with severe BPD (BPD-PH) and underwent bilateral lung transplantation (BLTx). Case description A 9-year-old girl was admitted to our department to undergo BLTx. She was born at 23 weeks and 4 days gestation with a weight of 507 g. She received ventilation for the first 2 months and required further respiratory care due to repetitive, severe respiratory infections. She was diagnosed with BPD-PH at 6 months of age and oral administration of pulmonary vasodilators were initiated. She was registered as a lung transplant candidate at 4 years of age after the life-threatening exacerbation. Chest computed tomography (CT) revealed severe lung conditions with ground-glass opacities and emphysematous low-density areas in the upper and lower lobes. BLTx from a brain-dead male donor was performed. The pathological findings of her resected lung revealed saccular, hypoplastic lung with alveolar repair/regeneration, and medial hypertrophy and muscularization of peripheral arteries. The postoperative course was mostly uneventful. She was free from oxygen administration and showed no signs of PH after 6 months of the surgery. Conclusion This is the first case report of BLTx in a pediatric, irreversible BPD-PH patient with detailed pathohistological findings and clinical examination. Lung transplantation is one of the treatment options for severe BPD-PH.

Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum β-D-glucan elevated without any sign of fungal infection by other tests. The serum β-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum β-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.

This study was performed to compare the outcome of lung transplantation (LT) for idiopathic pleuroparenchymal fibroelastosis (IPPFE) with that of LT for idiopathic pulmonary fibrosis (IPF). We reviewed, retrospectively, all adult patients who underwent LT for IPPFE or IPF in Japan between 1998 and 2018. There were 100 patients eligible for this study (31 with IPPFE and 69 with IPF). Patients with IPPFE tended to have a significantly lower body mass index (BMI) than those with IPF (median, 16.7 vs. 22.6 kg/m2, respectively; P

Objectives One of the serious problems after lung transplantation is chronic lung allograft dysfunction (CLAD). Most CLAD patients pathologically characterized by obliterative bronchiolitis (OB). Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4)-Ig is a combination protein of the Fc fragment of human IgG1 linked to the extracellular domain of CTLA4. The aim of the study was to examine the effect of CTLA4-Ig therapy on OB using a mouse intrapulmonary tracheal transplantation (IPTT) model. Methods IPTT was performed between BALB/c (donor) and C57BL/6 (recipient) mice. Abatacept, which is a commercially available form of CTLA4-Ig, was intraperitoneally injected in recipient mice immediately after surgery, on days 7, 14, and 21. The mice in the control group received human IgG. Results We performed semi-quantitative analysis of graft luminal obliteration at post-transplant day 28. We calculated the obliteration ratio of the lumen of the transplanted trachea in each case. The obliteration ratio was significantly lower in the CTLA4-Ig group than that in the control group (91.2 ± 2.1% vs. 47.8 ± 7.9%, p = 0.0008). Immunofluorescent staining revealed significantly decreased lymphoid neogenesis in the lung. Conclusions CTLA4-Ig therapy attenuated tracheal obliteration with fibrous tissue in the mouse IPTT model. The attenuation of fibrous obliteration was correlated with the inhibition of lymphoid neogenesis.

BACKGROUND Sirolimus and tacrolimus require accurate drug dosing based on their target blood levels to produce better clinical outcomes, specifically, the avoidance of drug-induced adverse effects and the maintenance of efficacy. However, because the ideal dose of sirolimus and the schedule for measuring its blood levels are unclear in lung transplant patients, an index is required for estimating sirolimus blood concentrations. The aim of this work is to study the correlation between the trough concentration/dose normalized by body weight (C0/D) ratios of sirolimus and tacrolimus in lung transplant patients. METHODS Thirteen lymphangiomyomatosis patients who underwent lung transplantation and were treated with sirolimus and tacrolimus from February 2015 to July 2018 were divided into 2 groups, one receiving twice-daily (TD, n = 6) and the other once-daily (OD, n = 7) tacrolimus formulations. The correlation between the C0/D ratio of sirolimus and patient background was evaluated using Spearman's rank correlation coefficient. Correlations between sirolimus and tacrolimus C0/D ratios or doses were analyzed by single regression analysis. RESULTS Significant correlations were found between the C0/D ratios of sirolimus and tacrolimus. The regression equations from the initial data of TD and OD groups at steady state were y = 1.880x + 32.636 (adjusted R = 0.743, P = 0.017) and y = 1.684x + 38.816 (adjusted R = 0.919, P < 0.001), respectively. In addition, the regression equations from all data of TD and OD groups were y = 1.883x + 4.170 (adjusted R = 0.546, P < 0.001) and y = 1.950x + 43.188 (adjusted R = 0.898, P < 0.001), respectively. A significant correlation between the dosage of sirolimus and tacrolimus was observed only in the OD group, with relatively low accuracy. CONCLUSIONS Blood sirolimus concentrations can be estimated using the C0/D ratio of tacrolimus, suggesting that the C0/D ratio of tacrolimus is an index of required sirolimus dosage and the frequency of blood sirolimus concentration measurements.

Appropriate selection for surgery is particularly important in T4 non-small cell lung cancer patients. In clinical settings, patients those who are positive for T4 criteria occasionally are also positive for T3 factors which are independently defined from original T4 or even have multiple T4 factors. Significance of these factors on prognosis is still unknown. We retrospectively reviewed clinicopathorogical data of 113 patients with T4 non-small cell lung cancer those who underwent surgery between 1990 and 2015 in Tohoku University Hospital. Significance on prognosis of single or multiple T4 factors and with or without independent T3 factors were statistically analyzed. No significant difference was seen in the 5-year survival rate between patients with single (35.6%) and multiple (31.4%) T4 factors (P = 0.94), but the rate was significantly lower when patients also had independent T3 factors (19.6%) compared with when they did not (42.5%) (P = 0.011). The 5-year survival rate was particularly lower among patients with invasion of the chest wall or parietal pleura (8.1%) than in those without (40.6%) (P = 0.0052). Invasion of the chest wall or parietal pleura is poor prognostic factors in T4 non-small cell lung cancer patients.

Background Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that occurs in premature infants and the prognosis is variable depending on the comorbidities including fibrosis, emphysema, or pulmonary hypertension (PH). We present a case of a 9-year-old girl who developed PH associated with severe BPD (BPD-PH) and underwent bilateral lung transplantation (BLTx). Case description A 9-year-old girl admitted to our department to undergo BLTx. She was born at 23 weeks and 4 days gestation with a weight of 507 grams. She received ventilation for the first 2 months and required further respiratory care due to repetitive, severe respiratory infections. She was diagnosed with BPD-PH at 6 months of age and oral administration of pulmonary vasodilators were initiated. She was registered as a lung transplant candidate at 4 years of age after the life-threatening exacerbation. Chest computed tomography (CT) revealed severe lung conditions with ground-glass opacities and emphysematous low-density areas in the upper and lower lobes. BLTx from a brain-dead male donor was performed. The pathological findings of her resected lung revealed saccular, hypoplastic lung with alveolar repair/regeneration and medial hypertrophy and muscularization of peripheral arteries. The postoperative course was mostly uneventful. She was free from oxygen administration and showed no signs of PH after 6 months of the surgery. Conclusion This is the first case report of BLTx in a pediatric, irreversible BPD-PH patient with detailed pathohistological findings and clinical examination. Lung transplantation is one of the treatment options for severe BPD-PH.

Solitary fibrous tumors are typically benign and usually develop in the pleura. We herein report the first case of a solitary fibrous tumor that was pathologically malignant and developed in the left atrial endocardium. A 24-year-old woman underwent resection of a malignant solitary fibrous tumor in her right forearm at another hospital. Computed tomography demonstrated a mass in her right pleura 2 months after the surgery. She was referred to our hospital, and a tumor in her left atrium was subsequently found. She underwent resection of these tumors, and pathological examination showed that they were both malignant solitary fibrous tumors.

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.

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.

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.

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.

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.

Both glandular papilloma (GP) and sclerosing pneumocytoma (SP) are rare tumors in the lung. We herein report an extremely rare case of coexistence of these two uncommon tumors. The patient was a 40-year-old Japanese woman with no chief complaint. A solitary nodule of the lung was detected using chest computed tomography. The transbronchial biopsy revealed that the tumor histologically corresponded to GP. The patient subsequently underwent partial resection of the right upper lobe. Histological examination of the resected specimens further revealed that the mass contained two different and independent elements and displayed typically histological features of GP and SP. Molecular analysis further revealed the presence of BRAF V600E and AKT1 E17K mutations in GP, whereas only AKT1 mutation was detected in SP. To our knowledge, this is the first case of coexistence of GP and SP in the bronchiole harboring common AKT1 mutation and different BRAF V600E mutational status.

Background Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 ± 2.73 μg/mL versus 2.82 ± 2.71 μg/mL, P

Purpose Idiopathic pleurparenchymal fibroelastosis (IPPFE) is a relatively new disease entity of interstitial pneumonia characterized by upper lobe dominant fibrosis and flat chest. The purpose of this study is to evaluate the outcome of lung transplantation for IPPFE in comparison with idiopathic pulmonary fibrosis (IPF). Methods We retrospectively reviewed patients with IPPFE and those with IPF aged 20 or over who underwent lung transplantation between 1998 and 2018. Data were collected from all nine lung transplant centers in Japan, under the support of Japanese Society of Lung and Heart-Lung Transplantation. Results One hundred patients were eligible, including 31 IPPFE and 69 IPF patients. Patients with IPPFE were more likely to be women (58% vs 28%; P Conclusion The survival of patients with IPPFE after lung transplantation was comparable with those with IPF. However, patients with IPPFE showed longer ICU stay, limited improvement in pulmonary function, and no improvement in low BMI, suggesting systemic or extrapulmonary problems such as stiff chest wall in patients with IPPFE.

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: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC 0-12 ) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC 0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. Methods: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC 0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). Results: The best three time-point equation was 4.04 + 1.64·C 1 + 3.08·C 4 + 5.17·C 8 for MPA, and -0.13 + 3.01·C 1 + 3.51·C 4 + 5.74·C 8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC 0-12 within ± 15% of the observed AUC 0-12 was 77.27% for MPA and 81.82% for AcMPAG. Conclusion: LSS using three time-point (C 1 , C 4 , and C 8 ) provides the most reliable and accurate simultaneous estimation of the AUC 0-12 of MPA and AcMPAG in Japanese lung transplant patients.

Purpose Lung transplantation (LTx) is an effective treatment for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). However, native lung-related complications, such as chylothorax, chylous sputum, and native lung hyperinflation, can develop after a single LTx. LAM lesion recurrence in transplanted lungs and abdominal LAM lesions may also occur post-LTx. Further, while sirolimus therapy can be used to treat these complications, its efficacy and tolerability in patients with LAM after LTx remain unclear. This study aimed to evaluate the effect of sirolimus on post-LTx LAM complications. Methods We retrospectively reviewed the records of LTx recipients who received sirolimus for treating post-LTx LAM complications from March 2000 to December 2019. Results Of the 40 patients who underwent LTx for LAM treatment, eight underwent sirolimus treatment for post-LTx LAM complications. Two patients exhibited chylous sputum; two, chylous ascites; one, chylothorax; one, native lung hyperinflation; one, LAM recurrence in the transplanted lung; and one, angiomyolipoma. Patients’ immunosuppressive regimen consisting of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids was not changed, but the target trough level of TAC was reduced with the baseline levels of TAC and sirolimus being 5 ng/mL each. Sirolimus was discontinued for one patient because nausea occurred soon after the first dose. LAM lesions improved or were suppressed in six patients (Figure 1). The forced expiratory volume at 1 s post-sirolimus administration was stable (Figure 2). Acute rejection and infection were not observed, but one patient underwent a second LTx on the contralateral side due to chronic lung allograft dysfunction. Conclusion Providing sirolimus immunosuppressive therapy after LTx for LAM treatment can be effective in managing post-LTx LAM complications and may be acceptable when combined with TAC, MMF, and steroids.

Increasing evidence suggests that interleukin (IL)-17A plays an important role in chronic lung allograft dysfunction (CLAD), characterized by airway and lung parenchymal fibrosis, after lung transplantation. Halofuginone is a plant derivative that has been shown to inhibit Th17 differentiation. The purpose of this study was to examine the effect of halofuginone on CLAD development using a minor alloantigen‒mismatched mouse orthotopic lung transplant model.C57BL/6 recipient mice received an orthotopic left lung transplant from C57BL/10 donors, mismatched for minor antigens. Lung transplant recipients received daily intraperitoneal injections of 2.5 μg halofuginone or vehicle alone. Lung grafts were assessed on Days 7, 14, and 28 post-transplant.Compared with control mice, on Day 28 post-transplant, lung grafts of mice treated with halofuginone showed a significant reduction in the percentage of obliterated airways (6.8 ± 4.7% vs 52.5 ± 13.8%, p0.01), as well as significantly reduced parenchymal fibrosis (5.5 ± 2.3% vs 35.9 ± 10.9%, p0.05). Immunofluorescent staining for IL-17A demonstrated a decreased number and frequency of IL-17A‒positive cells in halofuginone-treated lung grafts on Day 28, as compared with controls. Halofuginone treatment also decreased IL-17A and IL-22 transcripts at Day 14, transforming growth factor-β1 and matrix metalloproteinase-2 transcripts at Days 14 and 28.The beneficial effect of halofuginone on development of airway and lung parenchymal fibrosis in the mouse lung transplant model highlights the important role of IL-17A in CLAD and merits further pre-clinical and clinical studies.

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.

Background. Acute kidney injury (AKI) is a common complication after lung transplant (LTx), and continuous renal replacement therapy (CRRT) is increasingly of use to critically ill patients who have developed AKI. However, the optimal timing or threshold of kidney impairment for which to commence CRRT after LTx has been uncertain. There has also been limited information on the impact of CRRT among LTx recipients (LTRs) introduced in the early posttransplant period on survival, graft function, and renal function. We aimed to review LTRs who developed AKI requiring CRRT postoperatively and followed their long-term outcomes at Tohoku University Hospital (TUH). Methods. Medical records of consecutive patients who underwent LTx at TUH between 2000 and 2018 were reviewed, with follow-up to 2019 inclusive. Results. Although mortality in those who required CRRT (n = 21) was increased versus those who did not require CRRT (n = 85)(P = 0.024), conditional survival beyond 3-month posttransplant was not affected (P = 0.131). Additionally, the cumulative incidence of chronic lung allograft rejection (P = 0.160) and the development of chronic kidney disease (P = 0.757) were not significant between groups. Conclusions. The initiation of CRRT posttransplant may be a useful strategy to preserve cardiac and optimize volume management among critically ill patients.

Transplant recipients become immunocompromised through the use of immunosuppressive therapy to prevent allograft rejection. These recipients readily experience human cytomegalovirus (CMV) infection or reactivation. Therefore, CMV represents a life-threatening pathogen in transplant recipients. To demonstrate the serostatus and course of IgG maturation against CMV in transplant patients, we measured the transition of anti-CMV IgG and its affinity (avidity index; AI) as criteria for antibody maturation. Among 31 lung transplant recipients, 26 were infected with CMV before transplantation and maintained anti-CMV IgG and high AI values throughout the study period. Four of the 31 experienced primary infection with CMV through the allograft, with two of the 4 recipients presented high AI values even after 6 month post-transplantation. A significant portion of donor-derived plasma cells were detectable in one recipient. These results suggested that the plasma cells from donors are carried in through the transplanted lung and lymph nodes and produce matured high-avidity IgG from the early stage of transplantation.

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

Background Lung transplantation is an effective treatment modality for respiratory failure. Chronic lung infections, including infections caused by nontuberculous mycobacteria (NTM) and Aspergillus , are difficult to control, and uncontrolled infections are relative contraindications for lung transplantation. However, few reports have documented the incidence and outcome of these infections in lung transplant recipients. Methods To quantify the incidence and outcomes of colonization and disease caused by NTM and aspergillosis in recipients before and after lung transplantation, we reviewed the medical records and microbiology data from 240 consecutive cadaveric lung transplant recipients between 2000 and 2014. Results Before lung transplantation, NTM and Aspergillus species were isolated from five (2.1%) and six (2.5%) patients, respectively, out of the total 240 recipients. All patients with NTM infection received treatment, resulting in culture conversion. They had no recurrence after lung transplantation. All patients with aspergillosis received treatment, one of whom had recurrence after lung transplantation. Over a median follow-up period of 3.3 years, NTM species were isolated after transplantation from eight of 240 patients (3.3%). Five of these patients met the criteria for NTM disease, and four of them received treatment. Four patients survived without a worsening of NTM disease. Over the same median follow-up period, Aspergillus species were isolated from seven of 240 patients (2.9%), six of whom received treatment. Conclusions Isolation of NTM or Aspergillus species from lung transplant recipients is uncommon. Adequate pre-transplant control and post-transplant management of NTM and Aspergillus infections allows for safe lung transplantation.

Purpose CTLA4-Ig has been used as a treatment for rheumatoid arthritis in clinical practice. CTLA4-Ig was reported to induce lymphocyte-activation gene 3 positive regulatory T cells (LAG3+ Tregs), which produce high amounts of IL-10. This effect on LAG3+Tregs is thought to be one of the mechanisms of the therapeutic effect of CTLA4-Ig in rheumatoid arthritis patients. Recently, CTLA4-Ig was reported to improve long-term outcomes in kidney transplant recipients. We hypothesized that CTLA4-Ig can attenuate chronic lung allograft dysfunction (CLAD) after lung transplantation. The objective of this study was to investigate the effects of CTLA4-Ig therapy in a mouse intrapulmonary tracheal transplantation (IPTT) model, which is an animal model of CLAD. Methods C57BL/6 (B6) mice received IPTT from major-mismatched BALB/c donors. B6 mice were randomly divided into 2 groups. In the CTLA4-Ig group (n = 13) , recipient mice were intraperitoneally injected with 500 µg of CTLA4-Ig immediately after IPTT and on day 7, 14 and 21. In the control group, recipients (n = 11) were injected with 500 µg of human IgG in the same manner. After recipient animals were sacrificed on day 28, Masson's trichrome staining of the extracted left lung and semiquantitative analysis of the graft lumenal obliteration were conducted. Real-time PCR of the lung was performed (another set of groups were made for the analysis; CTLA4-Ig n = 9, control group n = 7). Results The lumenal obliteration ratio in the tracheal allografts was significantly reduced in the CTLA-Ig group (63.0 ± 7.51% vs. 90.1 ± 2.22%, p = 0.004) (Figure A, B). Real-time PCR of the lung revealed that the gene expression ratio of LAG3 to CD4 expression (LAG3/CD4) ratio was significantly upregulated in the CTLA4-Ig group (2.81 ± 0.71 vs. 0.98 ± 0.12, p = 0.041) (Figure C). Conclusion CTLA4-Ig attenuated the fibrous airway obliteration in the mouse IPTT model. CTLA4-Ig may promote LAG3+Treg-mediated anti-inflammatory effects.

Purpose Whereas native lung overinflation has been thought to happen in recipients of single lung transplantation for lymphangioleiomyomatosis because of its increased compliance, there is no study that has reported the details on the change of the native lung volume after single lung transplantation by three-dimensional computed tomography volumetry. The purpose of the present study was to evaluate the lung volume after single lung transplantation for lymphangioleiomyomatosis by three-dimensional computed tomography volumetry and investigate the correlation between the native lung volume change and postoperative pulmonary function. Methods We retrospectively reviewed the data of 17 patients who underwent single lung transplantation for lymphangioleiomyomatosis. We defined the ratio of the native lung volume to total lung volume (N/T ratio) as an indicator of overinflation of the native lung. In order to assess changes in the N/T ratio over time, we calculated the rate of change in the N/T ratio which is standardized by the N/T ratio at 1 year after single lung transplantation: rate of change in N/T ratio (%) = {(N/T ratio at a certain year)/(N/T ratio at 1 year)- 1}× 100. Results We investigated the correlations between the N/T ratio and the pulmonary function test parameters at 1 year and 5 years; however, there was no significant correlation between them. On the other hand, there was a significant negative correlation between the rate of change in the N/T ratio and that in forced expiratory volume in 1 second %predicted (%FEV1) at 5 years after single lung transplantation. Conclusion The single lung transplantation recipients for lymphangioleiomyomatosis showed increased rate of change in the N/T ratio in the long-time course after lung transplantation with the decrease of %FEV1. We expect that these cases will probably cause the overinflation of the native lung in the future.

Bronchiolitis obliterans after lung transplantation is a major cause of postoperative mortality in which T cell-mediated immunity is known to play an important role. However, the exact contribution of natural killer (NK) cells, which have functions similar to CD8+ T cells, has not been defined. Here, we assessed the role of NK cells in murine bronchiolitis obliterans through heterotopic tracheal transplantations and found a greater percentage of NK cells in allografts than in isografts. Depletion of NK cells using an anti-NK1.1 antibody attenuated bronchiolitis obliterans in transplant recipients compared with controls. In terms of NK cell effector functions, an improvement in bronchiolitis obliterans was observed in perforin-KO recipient mice compared to wild type (WT). Furthermore, we found upregulation of NKG2D-ligand in allografts and demonstrated the significance of this using grafts expressing Rae-1, a murine NKG2D-ligand, which induced severe bronchiolitis obliterans in WT and Rag-1 KO recipients. This effect was ameliorated by injection of anti-NKG2D blocking antibody. Together, these results suggest that cytotoxicity resulting from activation of NK cells through NKG2D leads to the development of murine bronchiolitis obliterans.

In solitary fibrous tumors (SFTs) of the pleura, malignant SFTs are uncommon. Although SFTs are known to cause paraneoplastic syndromes through the production of insulin-like growth factor, to the best of our knowledge, the production of beta-human chorionic gonadotropin (β-hCG) has been reported only in 1 case involving a patient with a benign SFT. We herein report the first case of the elevation of β-hCG serum levels associated with a malignant SFT in which the β-hCG serum level became a useful indicator of recurrence after the complete resection of the primary mediastinal lesion.

Trans-femoral amputees are needed to regain moving pattern by refined rehabilitation program using load conditions on a prosthetic limb with the artificial knee joint. On the other hand, understanding loads applied on a prosthetic limb is important for biomechanical consideration of trans-femoral amputees. However, conventional prosthetic gait training systems cannot measure long continuous walking motions under an outdoor environment. In this paper, loads applied on the intermediate part of trans-femoral prosthesis are measured by the prosthetic gait training system for the unrestrained gait measurement. As a result of the experiments, the patterns of moments about the medio-lateral axis along a gait cycle are remarkably different among the six activities. Finally, the effectiveness of the developed prosthetic gait training system is validated and the understanding of biomechanics in trans-femoral prosthesis during gait is increased. Loading data will be useful to refine the rehabilitation protocol for trans-femoral amputees with a prosthetic limb.

Inhaled drugs are critical for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). To develop better therapeutics for pulmonary disease it is of potential importance to understand molecular mechanisms of local biotransformation in the lung. Alveolar epithelial type II (ATII) cells have a key role in homeostasis in the lung, but little is known about expression patterns of genes encoding cytochrome P450 (CYP) enzymes in ATII cells. In addition, alteration of CYP gene expression has not been fully defined in COPD. We previously established a method to purify ATII cells from the adult human lung using fluorescence‐activated cell sorting. By employing this technique we determined gene expression patterns of 14 CYP enzymes in ATII cells from nonsmokers (n = 4) and smokers (n = 4), both having normal pulmonary function. Although most CYP genes are highly expressed in primary hepatocytes, we found that CYP1B1 mRNA expression was 7.2‐fold higher in ATII compared to hepatocytes (P = .0275). Additionally we noted a 3.0‐fold upregulation of CYP2C19 and 50% reduction in CYP2J2 mRNA expressions in ATII cells isolated from patients with COPD (n = 3) compared to smokers without COPD (n = 4). These data, for the first time, detail a comprehensive set of genes encoding CYP enzymes in human ATII cells and highlights differentially expressed CYP mRNAs of patients with COPD. Such understanding may have important implications for the development of novel inhaled drugs.

肺小細胞癌の集学的治療により寛解し，長期生存の得られたLambert-Eaton筋無力症の一例を経験した．本症例は原因不明の脱力により発症し，原発巣不明の小細胞癌の縦隔リンパ節転移に合併していた．右開胸を行い，右肺上葉に微小な原発巣を発見．完全切除を行った後，術後縦隔照射と全身化学療法を追加した．術後早期にproGRPは正常化したものの，抗VGCC抗体価は高値のままであった．抗VGCC抗体価が持続的に高値であるにもかかわらず，筋無力症状は軽快し，発症から6年間無再発生存している．このことからLambert-Eaton筋無力症の病因として，抗VGCC抗体のみが関与しているのでは無いということが示唆された．

Background Tranilast is an anti-allergic agent known to inhibit the release of histamine, interleukin-1β, transforming growth factor β1, and platelet-derived growth factor from various cells and currently is used to treat allergic diseases, keloids, and hypertrophic scars. We evaluated the ability of tranilast to inhibit the development of obliterative airway disease (OAD) in a rat model of heterotopic tracheal transplantation. Methods We transplanted tracheal segments from donor rats (Brown Norway) into subcutaneous pouches in major histocompatibility complex-incompatible recipient rats (Lewis). At Days 21 and 28 after transplantation, we histologically assessed the harvested allografts scored the degree of OAD, on a scale from zero to 4 as previously described, caused by fibroproliferative tissue. Results Recipient animals treated orally with 400 mg/kg/day tranilast throughout the experiment showed significantly decreased OAD compared with control animals, with a histologic score of 1.1 ± 0.4 vs 3.0 ± 1.3, respectively (mean ± SD, p = 0.007), at Day 21 after transplantation and 2.0 ± 1.4 vs 3.9 ± 0.4, respectively (mean ± SD, p = 0.017), at Day 28 after transplantation. Conclusion These results showed that treatment with tranilast significantly decreased fibroproliferative airway changes associated with allograft rejection in a rat model of tracheal transplantation, suggesting that tranilast may be useful in preventing bronchiolitis obliterans after lung transplantation.

11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11beta-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation.Controlled laboratory study.University research laboratory.Adult Sprague-Dawley rats (n = 66).Rats were intraperitoneally injected with carbenoxolone (2 x 10 mg.kg(-1).day(-1) for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg).We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of alpha-subunit, four-fold increase of beta-subunit, and two-fold increase of gamma-subunit) as well as in trachea. Carbenoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid.These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.

BACKGROUND Cold preservation is the most practical method to maintain the viability of isolated lungs. However, rapid cooling may affect pulmonary endothelial function. We examined the effects of microtubule stabilization with paclitaxel on pulmonary endothelial barrier integrity under cold temperature. METHODS Human pulmonary arterial endothelial cells were incubated at 4 degrees C for 2 hr in the presence or absence of paclitaxel (2.5 micromol/L). Microtubules was visualized using immunocytochemical techniques. Ultrasonic attenuation was measured with scanning acoustic microscopy. Endothelial barrier integrity was measured as transendothelial electric resistance. In addition, we examined graft function in a rat lung transplantation model, in which the donor lung had been preserved in the presence of paclitaxel (2.5 micromol/L) at 4 degrees C for 12 hr. RESULTS Low temperature caused a reversible microtubule disassembly, but the structure of microtubules was preserved by paclitaxel. Paclitaxel prevented the cooling-induced decrease in ultrasonic attenuation and transendothelial electric resistance. In a rat transplantation model, we found that preservation with paclitaxel successfully improved the oxygenation performance of the donor lung, which demonstrated only mild congestion and less significant interstitial edema without fluid accumulation in the alveolar spaces. CONCLUSIONS Our results indicate that microtubule stabilization with paclitaxel may be beneficial to prevent the loss of the endothelial barrier during cold preservation. We conclude that the use of paclitaxel in organ preservation solutions is useful in protecting pulmonary endothelial barrier integrity during cold preservation, thereby reducing the occurrence of early graft failure.

症例は29歳, 男性. トラック運転中に居眠りをして大型トラックに追突, ハンドルで前胸部を強打した. 近医に搬送され気管分岐部裂傷の診断を得て, 当科に紹介された.気管支鏡検査上, 気管分岐部竜骨の左右主気管支接合部が損傷し直径約8mmの裂孔が認められた.受傷約24時間後に手術を開始.竜骨の損傷が比較的広範なため, 明らかな損傷部のみのdebridementと単純縫合閉鎖では術後縫合不全や肉芽性狭窄の危険性が高いと考え, 気管分岐部を切除しMontage型再建術を行った.術後, 気管・気管支吻合部合併症をきたすことなく良好に経過し第29病日に退院した.気管分岐部損傷に対する分岐部切除再建術の報告はこれまでないが, 竜骨の広範な破壊を伴う症例に対しては, 積極的にこの術式を考慮してよいと考える.

Pulmonary arterial hypertension after arterial switch operation for transposition of the great arteries is an infrequent but life-threatening complication. We report successful lung transplantation in a case of pulmonary hypertension after arterial switch operation. Cardiopulmonary bypass outflow was established through the right subclavian and femoral arteries because of the previous arterial switch operation. Abnormal anatomy and severe pleural and pericardial adhesions as a result of previous operations resulted in prolonged graft ischemic and operation times. Despite delayed left heart adaptation and primary graft dysfunction requiring prolonged extracorporeal membrane oxygenation, the recipient was eventually discharged without activity limitations.

Lung transplantation is the final lifesaving option for patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT for hematologic diseases are thought to be high-risk candidates for lung transplantation; therefore, few lung transplants are performed for these patients, and few studies have been reported. This study aimed to describe the characteristics and outcomes of lung transplantation in patients with pulmonary complications after HSCT.We retrospectively investigated 62 patients who underwent lung transplantation after HSCT. All data were collected from 6 lung transplant centers in Japan.Seventeen patients underwent cadaveric lung transplantation, whereas 45 underwent living-donor lobar lung transplantation (LDLLT). In the LDLLT group, 18 patients underwent LDLLT after HSCT in which one of the donors had also served as a donor for HSCT. Seven patients underwent single LDLLT for which the donor was the same as the patient from whom stem cells were obtained for HSCT. Preoperative hypercapnia was observed in 52 patients (84%). Thirteen patients (21%) required mechanical ventilation preoperatively. Fifty-five patients underwent HSCT for hematologic malignancies, and 4 (7%) relapsed after lung transplantation. The 5-year survival rate was 64.2%. In a multivariable analysis, patients younger than 45 years and those with the same donor for both procedures exhibited significantly better survival (P = 0.012 and 0.041, respectively).Lung transplantation for pulmonary complications after HSCT was performed safely and yielded better survival, especially in younger recipients for whom both lung transplantation and HSCT involved the same donor.

Because the shortage of donor organs is especially serious in Japan, since 2002 a unique partnership between transplant consultant physicians and local physicians has been developed to maximize the organ utilization rate. Since 2011, more than 25 lung consultant physicians have been registered to specifically assess donor lungs and provide advice on intensive respiratory care to donors. In this study, we retrospectively reviewed the efficacy of this system for lung transplantation opportunities and outcomes. One hundred eighty-seven brain-dead lung donor candidates were chronologically divided into 3 phases: I (May 1998-November 2006) and II (December 2006-January 2011), before and after medical consultants requested that local physicians administer aggressive bronchial suctioning using bronchoscopy, respectively; and phase III (February 2011-January 2013), after the emergence of lung consultants. The lung utilization rate, Pao2/Fio2 ratio at the first and second brain death examinations and at the tertiary assessment before recovery, and graft survival were analyzed. The lung utilization rate was significantly higher in phases II and III than in phase I. In phases I and II, the Pao2/Fio2 ratio at the tertiary assessment was significantly lower than that at the first or the second brain death examination, whereas it did not worsen with time in phase III. Graft survival was significantly better in phases II and III than in phase I. Graft death due to primary graft dysfunction was significantly more frequent in phase I than in phases II and III. In conclusion, this system is effective in improving lung transplantation opportunities and outcomes.

In human gait motion analysis, which is one useful method for efficient physical rehabilitation to define various quantitative evaluation indices, ground reaction force, joint angle and joint loads are measured during gait. To obtain these data as unrestrained gait measurement, a novel gait motion analysis system using mobile force plates and attitude sensors has been developed. On the other hand, a human maintains a high correlation among the motion of all joints during gait. The analysis of the correlation in the recorded joint motion extracts a few simultaneously activating segmental coordination patterns, and the structure of the intersegmental coordination is attracting attention to an expected relationship with a control strategy. However, when the evaluation method using singular value decomposition has been applied to joint angles of the lower limb as representative kinematic parameters, joint moments related to the rotational motion of the joints have not yet been considered. In this paper, joint moments as kinetic parameters applied on the lower limb during gait of a normal subject and a trans-femoral amputee are analyzed under change in walking velocity by the wearable gait motion analysis system, and the effectiveness for quantitatively evaluate the rotational motion pattern in the joints of the lower limb by using joint moments is validated.

s S53 All 10 rejection samples (figure 1, shown in red) were associated with a DS-cfDNA level of greater then 1.3%, yielding a sensitivity of 100% and a specificity 80% (figure 2). Two of these demonstrated elevated DS-cfDNA before the onset of any clinical symptoms. Conclusion: DS-cfDNA has high sensitivity in the non-invasive detection of rejection. Patients with elevated DS-cfDNA but without rejection had a higher incidence of valvar regurgitation, quilty lesions, and graft vasculopathy suggesting the utility of DS-cfDNA as a biomarker for ongoing injury to the donor organ.

We have investigated lattice damage in reactive ion etched silicon by using x-ray crystal truncation rod (CTR) scattering. The x-ray intensity associated with the rod in the reciprocal space depends on the etching-induced lattice distortion. To estimate the magnitude of the lattice distortion, we analyzed the obtained data with a kinematic x-ray diffraction model on the assumption that the lattice distortion decays exponentially with the depth. We found that the lattice distortion extends to a depth of about 9 nm. In addition, we propose a method for quantitatively evaluating lattice damage based on our analysis. This method allows us to compare lattice damage among samples etched under different conditions. This study indicates that x-ray CTR experiments provide a useful means of characterizing lattice distortions near processed surfaces.

A new concept of epitaxial silicon (Si) wafers (NC epi) in which p/sup -/(n/sup -/) thin-film layers are grown on p/sup -/(n/sup -/) Czochralski (CZ)-Si substrates (substrate resistivity: approximately 10 /spl Omega/ cm) is proposed for metal oxide semiconductor (MOS) ultra large-scale integrated circuits (ULSI's) as a starting material. A thickness of 0.3-1 /spl mu/m for the epitaxial layer (p/sup -//p/sup -/ structure) is shown to be sufficient for improving the gate oxide integrity for MOS-ULSI's. The epitaxial layer grown on Si substrate greatly reduces weak spots in the gate oxide layer by covering microdefects in the CZ-Si represented by the crystal originated particle (COP). The p/sup -//p/sup $/thin-film epitaxial structure results in very controlled resistivity for the electrically active region in the device, which in turn results in a lower growth cost and higher feasibility for use in current ULSI's. The features of NC epi in combination with proximity gettering is presented. An application of NC epi in shallow-trench isolation processes is discussed, considering the retrograde-type well-tub. The amenability of epitaxial wafers to wafer enlargement (over 300 mm) is discussed to eliminate the bad effects of COP.